Method of treating a patient with a cyp3a4 substrate drug

ABSTRACT

The present disclosure provides for methods of treating a patient with a CYP3A4 substrate drug contraindicated for concomitant administration with a strong CYP3A4 inhibitor, wherein the patient is treated with multiple doses of posaconazole, stops posaconazole treatment, and then is treated with the CYP3A4 substrate drug. In some embodiments, treatment with the CYP3A4 substrate drug is delayed for about 2-21 after stopping posaconazole. In some embodiments, the patient is treated with or prescribed a reduced dose of the CYP3A4 substrate drug for about 2-21 after stopping posaconazole.

BACKGROUND

Posaconazole, also called Noxafil and Posanol, is indicated for theprophylaxis of invasive Aspergillus and Candida infections in patientswho are at high risk of developing these infections due to beingseverely immunocompromised, such as hematopoietic stem cell transplant(HSCT) recipients with graft-versus-host disease (GVHD) or those withhematologic malignancies with prolonged neutropenia from chemotherapy,for the treatment of oropharyngeal candidiasis (OPC), including OPCrefractory (rOPC) to itraconazole and/or fluconazole, the treatment ofinvasive aspergillosis, and the treatment of zygomycosis. Posaconazolehas also been used “off-label” for treating allergic bronchopulmonaryaspergillosis; prophylaxis or treatment of recurrent candidiasis for theesophagus, secondary to HIV infection; Fusarium infections mycosis; andchronic or cavitary necrotizing pulmonary aspergillosis.

Posaconazole is a strong inhibitor of the CYP3A4 enzyme, a member of thecytochrome P450 family of oxidizing enzymes found in the liver. TheseCytochrome P450 enzymes, such as CYP3A4, oxidize small organic moleculesin the body, such as toxins or certain drugs, thereby deactivatingand/or degrading them. Organic molecules in the body (such as a drug)which are primarily oxidized by a particular enzyme can be referred toas “substrates” for the relevant enzyme. A drug which is primarilyoxidized by the CYP3A4 enzyme can be referred to as a “CYP3A4 substratedrug.”

The Noxafil label specifically contraindicates the co-administration ofCYP3A4 substrate drug with specific drugs metabolized by CYP3A4 such assirolimus, CYP3A4 substrates such as pimozide and quinidine, HMG-CoAReductase Inhibitors primarily metabolized through CYP3A4, and ergotalkaloids, and indicates that dosage adjustments should be consideredwhen concomitantly administering posaconazole with other drugsmetabolized by CYP3A4, including Tacrolimus, cyclosporine, vincaalkaloids such as vincristine and vinblastine, and calcium channelblockers such as verapamil, diltiazem, nifedipine, nicardipine, andfelodipine. However, while the Noxafil label does identify specificdrug-drug interactions related to concomitant administration ofposaconazole and CYP3A4 substrate drugs, it does not indicate anyconcerns regarding the administration of CYP3A4 substrate drugs afterceasing the administration of posaconazole.

The present inventors have surprisingly discovered that a delay inadministration of a CYP3A4 substrate drug, or in some instances a doseadjustment of a CYP3A4 substrate drug for a specified time interval isrequired after ceasing the administration of posaconazole in order toprevent or reduce the incidence of dangerous side effects of the CYP3A4substrate drug.

SUMMARY OF THE INVENTION

The present disclosure provides for methods of treating a patient with aCYP3A4 substrate drug contraindicated for concomitant administrationwith a strong CYP3A4 inhibitor, wherein the patient was previouslyadministered a therapeutically effective regimen of posaconazole.

Applicants have discovered that although CYP3A4 substrate drugs aregenerally only contraindicated for coadministration with strong CYP3A4inhibitors, such as posaconazole, CYP3A4 substrate drugs cannot alwaysbe safely administrated immediately after a patient has stoppedposaconazole treatment. Applicants have discovered that posaconazoleaccumulation in the body of patients, particularly for specific patientpopulations as described herein, can result in serious and potentiallylife-threatening side effects if a CYP3A4 substrate drug is administeredtoo soon, subsequent to the cessation of a posaconazole regimen.Accordingly, for CYP3A4 substrate drugs, particularly thosecontraindicated for coadministration with a strong CYP3A4 inhibitor(including but not limited to posaconazole), a washout or delay periodof about 2-21 days between ceasing administration of the posaconazoleregimen and starting administration of the CYP3A4 substrate drug isrequired in order to avoid or reduce the incidence of side effectsresulting from administration of the CYP3A4 substrate drug.Alternatively, rather than delaying administering the CYP3A4 substratedrug after ceasing administration of the posaconazole regimen, in someembodiments, the Applicants have discovered that patients can safely beadministered a reduced dose of the CYP3A4 substrate drug (reducedrelative to the recommended dose of the CYP3A4 substrate drug) for aperiod of time (about 2-21 days) following cessation of the posaconazoleregimen, after which the dose of the CYP3A4 substrate drug can be safelyincreased to the recommended level.

In certain embodiments, the disclosed methods of delaying treatment witha CYP3A4 substrate drug, or reducing the dose of a CYP3A4 substratedrug, for about 2-21 days after ceasing administration of a posaconazoleregimen are directed to a normal patient, e.g., non-obese patients andnormal CYP3A4 metabolizers. In certain embodiments, the disclosedmethods of delaying treatment of a CYP3A4 substrate drug, or reducingthe dose of a CYP3A4 substrate drug, for about 2-21 days after ceasingadministration of a posaconazole regimen are directed to patients havingspecific physiological characteristics as described herein. Suchpatients can exhibit a substantially greater exposure to the CYP3A4substrate drug after ceasing administration of a posaconazole regimenthan was previously known, and therefore after ceasing administration ofposaconazole, require substantially longer “washout” periods prior tostarting treatment of a CYP3A4 substrate drug, or require treatment of areduced dose of the CYP3A4 substrate drug for a substantially longerperiod in order to avoid or reduce the incidence of side effectsassociated with treatment of the CYP3A4 substrate drug. Morespecifically, the present applicants have found that patients havingspecific physiological characteristics as described herein exhibithigher than expected exposure to a CYP3A4 substrate drug dosed afterceasing administration of a posaconazole regimen, compared to “normal”patients (e.g., a patient who is otherwise the same except for havingspecific physiological characteristics as described herein). Forexample, patients with e.g., BMI values in the “normal” range (about18.5-24.9) can exhibit substantially reduced CYP3A4 substrate drugelimination; such patients may be described as poor or intermediateCYP3A4 metabolizers. Thus, as disclosed herein, the present inventorshave found that specific patient populations may require substantiallydifferent and longer washout periods after ceasing administration ofposaconazole and prior to starting treatment with a CYP3A4 substratedrug, or alternatively treating with a reduced dose of a CYP3A4substrate drug for a particular period of time after stoppingposaconazole treatment.

In various embodiments, the present disclosure provides for methods oftreating a patient by delaying a first use of a CYP3A4 substrate druguntil about 2-21 days after stopping administration of posaconazole. Inembodiments, the CYP3A4 substrate drug is a drug contraindicated forconcomitant use with a strong CYP3A4 inhibitor, such as but not limitedto posaconazole. Accordingly, in various embodiments, the presentdisclosure provides for methods of treating a patient who has previouslybeen treated with multiple doses of posaconazole, with a CYP3A4substrate drug contraindicated for concomitant treatment with a strongCYP3A4 inhibitor, said method comprising first treating the patient, orprescribing the first treatment to begin, with a dose of the CYP3A4substrate drug at least 2-21 days after stopping a posaconazoletreatment.

In various embodiments, the present disclosure provides for methods oftreating a patient, or prescribing the first treatment to begin, with aCYP3A4 substrate drug at a dose which is less than or equal to about 50%of the reference dose, e.g., for a period of at least about 2-21 daysafter stopping posaconazole treatment. Accordingly, in variousembodiments, the methods include treating, or prescribing the firsttreatment to begin, with a therapeutically effective amount of a CYP3A4substrate drug contraindicated for concomitant use with a strong CYP3A4inhibitor to a patient in need thereof. In some embodiments, the patienthas previously been treated with posaconazole. In some embodiments, thepatient is treated, or prescribed to be treated, with a CYP3A4 substratedrug at a dose which is no more than about 50% of the reference dose forat least about 2-21 days after discontinuation of the posaconazoleregimen.

In various embodiments, the present disclosure provides for methods oftreating patients, or prescribing treatment for patients, having adisease or condition selected from the group consisting of schizophreniain adults and adolescents (13 to 17 years), depressive episodesassociated with Bipolar I Disorder (bipolar depression) in adults,monotherapy or adjunctive therapy with lithium or valproate, chronicangina, cystic fibrosis in patients 6 years and older who are homozygousfor the F508del mutation in the CFTR gene, chronic lymphocytic leukemiain patients with 17p deletion, who have received at least one priortherapy, unresectable or metastatic liposarcoma or leiomyosarcoma inpatients who received a prior anthracycline-containing regimen, advancedor metastatic breast cancer in postmenopausal women with hormonereceptor (HR)-positive, human epidermal growth factor receptor 2(HER2)-negative advanced or metastatic breast cancer, negative advancedor metastatic breast cancer in combination with an aromatase inhibitorfor postmenopausal women, Duchenne muscular dystrophy (DMD), secondaryhyperparathyroidism (HPT) in patients with chronic kidney disease (CKD)on dialysis, hypercalcemia in patients with parathyroid carcinoma or inpatients with primary HPT for who parathyroidectomy would be indicatedon the basis of serum calcium levels, but who are unable to undergoparathyroidectomy, hallucinations and delusions associated withParkinson's disease psychosis, schizophrenia, acute manic or mixedepisodes associated with bipolar I disorder, chronic hepatitis C (CHC)infection as a component of a combination antiviral treatment regimenwith peginterferon alfa and ribavirin in HCV genotype 1 infectedsubjects with compensated liver disease, postmenopausal women withadvanced hormone receptor-positive, HER2-negative breast cancer(advanced HR+BC), e.g., in combination with exemestane after failure oftreatment with letrozole or anastrozole, progressive neuroendocrinetumors of pancreatic origin (PNET), progressive, well-differentiated,non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) orlung origin that are unresectable, locally advanced or metastatic,advanced renal cell carcinoma (RCC), e.g., after failure of treatmentwith sunitinib or sorafenib, renal angiomyolipoma and tuberous sclerosiscomplex (TSC), not requiring immediate surgery, TSC in patients who havesubependymal giant cell astrocytoma (SEGA) that require therapeuticintervention but are not candidates for surgical resection, type 2diabetes mellitus in adults as an adjunct to diet and exercise toimprove glycemic control, major depressive disorder (MDD), thromboticcardiovascular events (e.g., cardiovascular death, myocardialinfarction, or stroke) in patients with acute coronary syndrome (ACS),stroke and systemic embolism in patients with nonvalvular atrialfibrillation, deep vein thrombosis (DVT), which may lead to pulmonaryembolism (PE) in patients who have undergone hip or knee replacementsurgery, DVT, PE, recurrent DVT and PE following initial therapy,moderate to severe active rheumatoid arthritis in patients who have hadinadequate response or tolerance to methotrexate, acute migraine with orwithout aura, chronic phase and accelerated phase Philadelphiachromosome positive chronic myeloid leukemia (Ph+CML) in newly diagnosedpatients or in patients resistant to or intolerant to prior therapy thatincluded imatinib, atrial fibrillation (AF) in patients with a historyof paroxysmal or persistent AF or atrial flutter (AFK), who are in sinusrhythm or will be cardioverted, asthma in patients aged 4 years andolder, airflow obstruction and reducing exacerbations in patients withchronic obstructive pulmonary disease, erectile dysfunction (ED), benignprostatic hyperplasia (BPH), pulmonary arterial hypertension (PAH) (WHOGroup 1) to improve exercise ability, gout flares, FamilialMediterranean fever, antiretroviral therapy, anxiety disorders, panicdisorders, seizures, insomnia, hypertension, cardiovascular disease,hyperlipidemia, cancer, such as primary kidney cancer, advanced primaryliver cancer, radioactive iodine resistant advanced thyroid carcinoma,renal cell carcinoma, imatinib-resistant gastrointestinal stromal tumor,mantle cell lymphoma in patients who have received at least one priortherapy, chronic lymphocytic leukemia/small lymphocytic lymphoma,chronic lymphocytic leukemia/small lymphocytic lymphoma with 17pdeletion, Waldenström's macroglobulinemia, marginal zone lymphoma whorequire systemic therapy and have received at least one prioranti-CD20-based therapy, unresectable or metastatic melanoma with a BRAFV600E or V600K mutation, allergies, and transplantation. In someembodiments, the methods include treating the disease or condition witha CYP3A4 substrate drug which is contraindicated for concomitant usewith a strong CYP3A4 inhibitor, wherein the patient is also in need oftreatment with a strong CYP3A4 inhibitor (i.e., posaconazole). In someembodiments, the methods include (a) delaying a first treatment of theCYP3A4 substrate drug for at least about 2-21 days after stoppingposaconazole; and then (b) treating, or prescribing a first treatment,with the CYP3A4 substrate drug. In other embodiments, the methodsinclude (a) delaying a first treatment of the CYP3A4 substrate drug forat least about 2-21 days after stopping administration of theposaconazole regimen, and then (b) treating or prescribing a firsttreatment the CYP3A4 substrate drug at a dose which is less than orequal to about 50% of the reference dose for at least about 2-21 daysafter stopping administration of the posaconazole regimen.

DETAILED DESCRIPTION

All documents, including patents, applications, and non-patentpublications cited herein are incorporated herein in their entiretiesfor all purposes.

As used herein, the term “about” refers to an amount somewhat more orless than the stated parameter value, for example plus or minus five orten percent of the object that “about” modifies, or as one of skill inthe art would recognize from the context (e.g., approximately 50% of theinterval between values). The term “about” also includes the valuereferenced. For example, a BMI of about 40 includes 40, as well asvalues somewhat below or above 40.

As used herein, the term “patient” refers to a human subject. In someembodiments, the patient can be a male or a female. In some embodiments,the patient can be an adult, or a pediatric patient.

As used herein “treating or “prescribing” as it pertains to the CYP3A4substrate drug during the 2-21 day period after ceasing posaconazoletreatment, refers to the overall therapeutic regimen of the CYP3A4substrate drug. For example, a patient may be prescribed or administered(including self-administering) a reduced dose of the CYP3A4 substratedrug (e.g., no more than about 50% of the reference dose of the CYP3A4substrate drug) during this period. In some embodiments, the patientwould not be administered, or would, in the physician's prescribeddosing regimen, be advised not to take the CYP3A4 substrate drug duringthe 2-21 day period; afterwards, the patient could (or would beprescribed to) resume taking e.g., the reference amount of the CYP3A4substrate drug.

As used herein, the terms “treating,” “treatment” and “treat” include(i) preventing a particular disease or disorder from occurring in asubject who may be predisposed to the disease or disorder but has notyet been diagnosed as having it; (ii) curing, treating, or inhibitingthe disease, i.e., arresting its development; or (iii) ameliorating thedisease by reducing or eliminating symptoms, conditions, and/or bycausing regression of the disease. In some embodiments, “treating,”“treatment” and “treat” may include administering a therapeuticallyeffective regimen as defined herein.

As used herein, a “therapeutically effective regimen” refers to atreatment regimen of a duration and dosage sufficient to treat a diseaseor condition for which a drug is prescribed.

As used herein, a “patient” refers to human subject that has anindication amendable to treatment with posaconazole and is also in needof treatment with a CYP3A4 substrate drug. For example, the patient,prior to being treated with or prescribed posaconazole, cansimultaneously have a first indication amendable to treatment withposaconazole and a second indication amendable to treatment the CYP3A4substrate drug. In some such embodiments, the patient is first treatedwith posaconazole, and then, after stopping the posaconazole regimen,the patient is switched to a treatment described herein for the CYP3A4substrate drug. In other embodiments, the patient, while being treatedwith posaconazole, develops an indication amendable to treatment with aCYP3A4 substrate drug. In some such embodiments, after stopping theposaconazole regimen, the patient is switched to a treatment descriedherein for the CYP3A4 substrate drug. As used herein, a “patient” doesnot include a subject that, at some point after stopping posaconazoletreatment, subsequently develops an indication which is amendable totreatment with a CYP3A4 substrate drug.

As used herein, a “patient treated with posaconazole” or a “patientpreviously on posaconazole” refers to a patient having an indicationwhich was amenable to treatment with posaconazole.

As used herein, the term “normal baseline C_(max)” refers to the averageC_(max) of a drug measured at the same dosage in an otherwise identicalpatient which was not previously treated with the strong CYP3A4inhibitor (e.g., posaconazole). For example, when the CYP3A4 substratedrug is ranolazine, the “normal baseline C_(max)” of ranolazine refersto the average C_(max) of ranolazine measured at the same dosage ofranolazine in an otherwise identical patient which was not previouslytreated with the strong CYP3A4 inhibitor (e.g., posaconazole). Asanother example, when the CYP3A4 substrate drug is lurasidone, the“normal baseline C_(max)” of lurasidone refers to the average C_(max) oflurasidone measured at the same dosage of lurasidone in an otherwiseidentical patient which was not previously treated with the strongCYP3A4 inhibitor (e.g., posaconazole). As another example, when theCYP3A4 substrate drug is tadalafil, the “normal baseline C_(max)” oftadalafil refers to the average C_(max) of tadalafil measured at thesame dosage of tadalafil in an otherwise identical patient which was notpreviously treated with the strong CYP3A4 inhibitor (e.g.,posaconazole).

As used herein, the term “normal baseline AUC” refers to the average AUCof a drug measured at the same dosage in an otherwise identical patientwhich was not previously treated with the strong CYP3A4 inhibitor (e.g.,posaconazole). For example, when the CYP3A4 substrate drug isranolazine, the “normal baseline AUC” of ranolazine refers to theaverage AUC of ranolazine measured at the same dosage of ranolazine inan otherwise identical patient which was not previously treated with thestrong CYP3A4 inhibitor (e.g., posaconazole). As another example, whenthe CYP3A4 substrate drug is lurasidone, the “normal baseline AUC” oflurasidone refers to the average AUC of lurasidone measured at the samedosage of lurasidone in an otherwise identical patient which was notpreviously treated with the strong CYP3A4 inhibitor (e.g.,posaconazole). As another example, when the CYP3A4 substrate drug istadalafil, the “normal baseline AUC” of tadalafil refers to the averageAUC of tadalafil measured at the same dosage of tadalafil in anotherwise identical patient which was not previously treated with thestrong CYP3A4 inhibitor (e.g., posaconazole).

As used herein, “normal,” “reference,” or other derivations orvariations thereof refers to a non-obese state in a person who can haveat least one of the following characteristics: BMI less than about 35, %IBW less than about 150%, waist size less than about 42, % body fat lessthan about 40%, % android body fat less than about 40%, % gynoid bodyfat less than about 40%, and total body fat less than about 40 kg.Unless otherwise modified “normal metabolizer” also means an extensiveCYP3A4 metabolizer.

As used herein, a “reference dose” refers to the dosage of a particularCYP3A4 substrate drug, as indicated on the manufacture's FDA-approvedlabel, prescribed for an identical patient not previously treated withthe strong CYP3A4 inhibitor (e.g., posaconazole).

Disclosed herein are methods of treating, or prescribing treatment for,a patient with a CYP3A4 substrate drug contraindicated for concomitantadministration with a strong CYP3A4 inhibitor, wherein the patient waspreviously treated with posaconazole, particularly when patients havingone or more of the physiological characteristics described herein aresubsequently treated with a CYP3A4 substrate drug. That is, thedisclosure provides for methods of treating different patientpopulations—e.g., “normal” patients, obese patients, and/or intermediateor worse (e.g., poor) CYP3A4 metabolizers—with a CYP3A4 substrate drugcontraindicated for concomitant administration with a strong CYP3A4inhibitor after said patient has ceased posaconazole treatment. Methodsof initiating treatment with a CYP3A4 substrate drug intended to treatvarious conditions or disorders in patients previously treated withposaconazole are also described herein. The present disclosure alsoprovides methods of preventing or decreasing the risk of side effectsassociated with overexposure to a CYP3A4 substrate drug in normalpatients, obese patients and/or patients with impaired CYP3A4 function(e.g., poor or intermediate CYP3A4 metabolizers) and who had previouslybeen treated with a posaconazole regimen prior to treating orprescribing a CYP3A4 substrate drug to said patient. (including thosefor treating conditions described herein).

In various embodiments, the present disclosure provides methods fortreating, or prescribing treatment for, a patient who had been treatedwith a therapeutically effective posaconazole regimen with a CYP3A4substrate drug, after a “washout” period of about 2-21 days afterceasing administration of posaconazole. This washout period allows forthe blood plasma concentrations of posaconazole to be reduced toappropriate levels after which a CYP3A4 substrate drug can beadministered without creating an elevated risk of serious side effectsfrom the CYP3A4 substrate drug. As described herein, the presentApplicants have found that CYP3A4 substrate drugs can be safelyadministrated to a patient previously treated with posaconazole, byfirst treating, or prescribing a first treatment, with the CYP3A4substrate drug (i.e., initiating the treatment with the CYP3A4 substratedrug) following a “washout” period of about 2-21 days starting at thetime the patient has stopped posaconazole treatment. However, the needfor such a washout period has been hitherto unknown, as such CYP3A4substrate drugs are conventionally contraindicated for concomitantadministration with posaconazole. As also described herein, in someembodiments the present Applicants have found that instead of a washoutperiod, the CYP3A4 substrate drug can potentially be safelyadministrated to a patient previously treated with posaconazole, at adose which is no more than about 50% of the reference dose of the CYP3A4substrate drug for a period of about 2-21 days after ceasing theposaconazole treatment. Similarly, such a dosing regime has beenhitherto unknown.

Cytochrome P450 3A4 (CYP3A4) is an enzyme that modifies small organicmolecules, such as particular drugs (specifically including drugsreferred to herein as “CYP3A4 substrate drugs”), so that the moleculesare metabolized and eliminated from the body. Some substances, termed“CYP3A4 inhibitors,” reduce the activity of the CYP3A4 enzyme, andtherefore these CYP3A4 inhibitors can increase the exposure of a patientto CYP3A4 substrate drugs. Strong CYP3A4 inhibitors can deactivateCYP3A4 if administered in an appropriate dose, which can result inexcessive and potentially dangerous blood plasma levels of aconcomitantly administered CYP3A4 substrate drugs. Consequently,concomitant administration of CYP3A4 substrate drugs is contraindicatedwith strong CYP3A4 inhibitors.

As used herein, a “strong CYP3A4 inhibitor” refers to a drug deemed soby the FDA and/or which causes at least about a 5-fold increase in theAUC of a sensitive CYP3A4 substrate drug, or more than about an 80%decrease in the clearance of a sensitive CYP3A4 substrate drug. Themethods disclosed herein can be applied to treat a patient with anyCYP3A4 substrate drug which is contraindicated for concomitantadministration with any strong CYP3A4 inhibitor, wherein the patient hasbeen treated with a strong CYP3A4 inhibitor, such as posaconazole.

Co-administration of posaconazole and CYP3A4 substrate drugs known toprolong the QTc interval are contraindicated. The presence ofconcomitant and clinically significant plasma levels of posaconazole andsuch CYP3A4 substrate drugs can result in significantly elevated levelsof the CYP3A4 substrate drug, which creates a risk of prolonging QT.Consequences of prolonged QT include arrhythmias, rapid heartbeat,abnormal heart rhythm, heart palpitations, dizziness, lightheadedness,sudden fainting, seizure, torsades de pointes, and cardiac death.

For example, according to the drug label for posaconazole (NOXAFIL®label, revised November 2015), patients are advised not to co-administerspecific CYP3A4 substrate drugs such as serolimus, pimozide, quinidine,HMG-CoA reductase inhibitors, ergot alkaloids, or drugs known to prolongthe QTc interval and cause cases of TdP, with posaconazole. The NOXAFIL®label also warns that dose adjustments should be considered forconcomitant administration of posaconazole and other drugs metabolizedby CYP3A4 such as tacrolimus, cyclosporine, vinca alkaloids, and calciumchannel blockers. However, the drug label of posaconazole does notrecognize that any washout period or any stratification of the patientpopulations are required after ceasing administration of posaconazoleand before initiating administration of a CYP3A4 substrate.

In some embodiments, the strong CYP3A4 inhibitor is posaconazole (i.e.,Noxafil, Posanol). Posaconazole is currently formulated as an oralsuspension solution (40 mg/mL), and intravenous solution (18 mg/mL), anddelayed release tablets (100 mg). According to the drug label (Merck &Co., Inc.,), current recommended dosing levels for prophylaxis ofinvasive Aspergillus and Candida infections by intraveneous injection orby delayed-release tablet are 300 mg twice a day on the first day and300 mg once a day thereafter, or 200 mg three times a day by oralsuspension. Current recommended dosing levels for treatment oforopharyngeal candidiasis by oral suspension are 100 mg twice a day onthe first day and 100 mg once a day for 13 days. Current recommendeddosing levels for treatment of oropharyngeal candidiasis refractory toitraconazole and/or fluconazole by oral suspension is 400 mg twice aday.

In some embodiments, posaconazole can be indicated for the treatment offungal infections. In one embodiment, posaconazole can be indicated forthe treatment of infections caused by Candida, e.g., oropharyngealcandidiasis. In one embodiment, posaconazole can be indicated for thetreatment of oropharyngeal candidiasis which is refractory toitraconazole and/or fluconazole. In one embodiment, posaconazole can beindicated for the treatment of infections caused by Aspergillus. In oneembodiment, posaconazole can be indicated for the treatment ofinfections caused by Zygomycetes. In some embodiments, posaconazole canbe indicated for the prophylaxis of Aspergillus or Candida infections,e.g., in immunocompromised patients at high risk of developing suchinfections, such as hematopoietic stem cell transplant (HSCT) recipientswith graft-versus-host disease (GVHD) or patients with hematologicmalignancies with prolonged neutropenia from chemotherapy. In oneembodiment, posaconazole can be indicated for the treatment ofzygomycosis. In one embodiment, posaconazole can be indicated for thetreatment of allergic bronchopulmonary aspergillosis. In one embodiment,posaconazole can be indicated for the treatment or prophylaxis ofrecurrent candidiasis for the esophagus, secondary to HIV infections. Inone embodiment, posaconazole can be indicated for the treatment ofFusarium infections mycosis. In one embodiment, posaconazole can beindicated for the treatment of and chronic or cavitary necrotizingpulmonary aspergillosis.

As used herein, a “CYP3A4 substrate drug” refers to any drug which isprimarily metabolized by the CYP3A4 enzyme which is administered in anypharmaceutically acceptable formulation (e.g. tablet, capsule, oralsolution, injection, infusion, or delayed or extended releaseformulations thereof). In some embodiments, the CYP3A4 drug islurasidone (Latuda). In some embodiments, the CYP3A4 is ranolazine(Ranexa). In some embodiments, the CYP3A4 substrate drugs can includelumacaftor/ivacaftor (Orkambi). In some embodiments, the CYP3A4substrate drugs can include venetoclax (Venclexta). In some embodiments,the CYP3A4 substrate drugs can include trabectedin (Yondelis). In someembodiments, the CYP3A4 substrate drugs can include ribociclib succinate(Kisqali). In some embodiments, the CYP3A4 substrate drugs can includedeflazacort (Emflaza). In some embodiments, the CYP3A4 substrate drugscan include cinacalcet hydrochloride (Sensipar). In some embodiments,the CYP3A4 substrate drugs can include pimavanserin tartrate (Nuplazid).In some embodiments, the CYP3A4 substrate drugs can include aripiprazolelauroxil (Aristada). In some embodiments, the CYP3A4 substrate drugs caninclude cariprazine hydrochloride (Vraylar). In some embodiments, theCYP3A4 substrate drugs can include simeprevir sodium (Olysio). In someembodiments, the CYP3A4 substrate drugs can include everolimus(Afinitor, Afinitor Disperz, Zortress). In some embodiments, the CYP3A4substrate drugs can include saxagliptin hydrochloride (Onglyza). In someembodiments, the CYP3A4 substrate drugs can includesaxagliptin/metformin hydrochloride (Kombiglyze XR). In someembodiments, the CYP3A4 substrate drugs can include ticagrelor(Brilinta). In some embodiments, the CYP3A4 substrate drugs can includevilazodone hydrochloride (Viibryd). In some embodiments, the CYP3A4substrate drugs can include apixaban (Eliquis). In some embodiments, theCYP3A4 substrate drugs can include tofacitinib citrate (Xeljanz). Insome embodiments, the CYP3A4 substrate drugs can include eletriptanhydrobromide (Relpax). In some embodiments, the CYP3A4 substrate drugscan include nilotinib hydrochloride monohydrate (Tasigna). In someembodiments, the CYP3A4 substrate drugs can include dronedaronehydrochloride (Multaq). In some embodiments, the CYP3A4 substrate drugscan include fluticasone propionate/salmeterol xinafoate (Advair Diskus).In some embodiments, the CYP3A4 substrate drugs can include rivaroxaban(Xarelto). In some embodiments, the CYP3A4 substrate drugs can includetadalafil (Cialis, Adcirca). In some embodiments, the CYP3A4 substratedrugs can include colchicine (Colcrys). In some embodiments, the CYP3A4substrate drugs can include ibrutinib (Imbruvica). In some embodiments,the CYP3A4 substrate drugs can include cobimetinib (Cotellis). Othernon-limiting examples of CYP3A4 substrate drugs include HIV proteaseinhibitors, such as amprenavir (Agenerase), atazanavir (Reyataz),darunavir (Prezista), fosamprenavir (Lexiva, Telzir), indinavir(Crixivan), lopinavir (Kaletra), nelfinavir (Viracept), ritonavir(Norvir), saquinavir (Invirase, Forovase), and tipranavir (Aptivus),benzodiazepines, such as alprazolam (Xanax), clonazepam (Klonopin), anddiazepam (Valium), calcium channel blockers such as amlodipine(Norvasc), aranidipine (Sapresta), azelnidipine (Calblock), barnidipine(HypoCa), benidipine (Coniel), cilnidipine (Atelec, Cinalong, Siscard),clevidipine (Cleviprex), isradipine (DynaCirc, Prescal), efonidipine(Landel), felodipine (Plendil), lacidipine (Motens, Lacipil),lercanidipine (Zanidip), manidipine (Calslot, Madipine), nicardipine(Cardene, Carden SR), nifedipine (Procardia, Adalat), nilvadipine(Nivadil), nimodipine (Nimotop), nisoldipine (Baymycard, Sular, Syscor),nitrendipine (Cardif, Nitrepin, Baylotensin), and pranidipine (Acalas),hydroxymethylglutaryl coenzyme A-reductase inhibitors, such asatorvastatin (Lipitor, Ator), lovastatin (Mevacor, Altocor, Altoprev),mevastatin (Compactin) and simvastatin (Zocor, Lipex), antineoplasticdrugs, such as sorafenib (Nexavar) and sunitinib (Sutent), nonsedatingantihistamines, such as fexofenadine (Allegra), loratadine (Claritin),desloratadine (Clarinex), cetirizine (Zyrtec), levocetirizine (Xyza) andimmunosuppressants, such as cyclosporin.

In some embodiments, the CYP3A4 substrate drug used in the methodsdisclosed herein can be any drug metabolized by CYP3A4, in particulardrugs metabolized by CYP3A4 and which are contraindicated for use withstrong CYP3A4 inhibitors or include dose adjustment recommendations forconcomitant administration with CYP3A4 inhibitors. In some embodiments,the methods described herein can be applied to any therapeutic regimenin which one or more CYP3A4 substrate drug(s) described herein are usedto treat a patient previously on posaconazole, including therapeuticregimens that entail treating a patient with a CYP3A4 substrate drug incombination with other drugs.

In some embodiments, the CYP3A4 substrate drug can be indicated for thetreatment of disease or condition selected from the group consisting ofschizophrenia in adults and adolescents (13 to 17 years), depressiveepisodes associated with Bipolar I Disorder (bipolar depression) inadults, as monotherapy or adjunctive therapy with lithium or valproate,chronic angina, cystic fibrosis in patients 6 years and older who arehomozygous for the F508del mutation in the CFTR gene, chroniclymphocytic leukemia in patients with 17p deletion, who have received atleast one prior therapy, unresectable or metastatic liposarcoma orleiomyosarcoma in patients who received a prior anthracycline-containingregimen, advanced or metastatic breast cancer in postmenopausal womenwith hormone receptor (HR)-positive, human epidermal growth factorreceptor 2 (HER2)-negative advanced or metastatic breast cancer,negative advanced or metastatic breast cancer in combination with anaromatase inhibitor for postmenopausal women, Duchenne musculardystrophy (DMD), secondary hyperparathyroidism (HPT) in patients withchronic kidney disease (CKD) on dialysis, hypercalcemia in patients withparathyroid carcinoma or in patients with primary HPT for whoparathyroidectomy would be indicated on the basis of serum calciumlevels, but who are unable to undergo parathyroidectomy, hallucinationsand delusions associated with Parkinson's disease psychosis,schizophrenia, acute manic or mixed episodes associated with bipolar Idisorder, chronic hepatitis C (CHC) infection as a component of acombination antiviral treatment regimen with peginterferon alfa andribavirin in HCV genotype 1 infected subjects with compensated liverdisease, advanced hormone receptor-positive, HER2-negative breast cancer(advanced HR+BC) in postmenopausal women in combination with exemestaneafter failure of treatment with letrozole or anastrozole, progressiveneuroendocrine tumors of pancreatic origin (PNET), progressive,well-differentiated, non-functional neuroendocrine tumors (NET) ofgastrointestinal (GI) or lung origin that are unresectable, locallyadvanced or metastatic, advanced renal cell carcinoma (RCC), e.g., afterfailure of treatment with sunitinib or sorafenib, renal angiomyolipomaand tuberous sclerosis complex (TSC), not requiring immediate surgery,TSC in patients who have subependymal giant cell astrocytoma (SEGA) thatrequire therapeutic intervention but are not candidates for surgicalresection, type 2 diabetes mellitus in adults as an adjunct to diet andexercise to improve glycemic control, major depressive disorder (MDD),thrombotic cardiovascular events (e.g., cardiovascular death, myocardialinfarction, or stroke) in patients with acute coronary syndrome (ACS),stroke and systemic embolism in patients with nonvalvular atrialfibrillation, deep vein thrombosis (DVT), which may lead to pulmonaryembolism (PE) in patients who have undergone hip or knee replacementsurgery, DVT, PE, recurrent DVT and PE following initial therapy,moderate to severe active rheumatoid arthritis in patients who have hadinadequate response or tolerance to methotrexate, acute migraine with orwithout aura, chronic phase and accelerated phase Philadelphiachromosome positive chronic myeloid leukemia (Ph+CML) in newly diagnosedpatients or in patients resistant to or intolerant to prior therapy thatincluded imatinib, atrial fibrillation (AF) in patients with a historyof paroxysmal or persistent AF or atrial flutter (AFK), who are in sinusrhythm or will be cardioverted, asthma in patients aged 4 years andolder, airflow obstruction and reducing exacerbations in patients withchronic obstructive pulmonary disease, erectile dysfunction (ED), benignprostatic hyperplasia (BPH), pulmonary arterial hypertension (PAH) (WHOGroup 1) to improve exercise ability, gout flares, FamilialMediterranean fever, antiretroviral therapy, anxiety disorders, panicdisorders, seizures, insomnia, hypertension, cardiovascular disease,hyperlipidemia, cancer, such as primary kidney cancer, advanced primaryliver cancer, radioactive iodine resistant advanced thyroid carcinoma,renal cell carcinoma, imatinib-resistant gastrointestinal stromal tumor,mantle cell lymphoma in patients who have received at least one priortherapy, chronic lymphocytic leukemia/small lymphocytic lymphoma,chronic lymphocytic leukemia/small lymphocytic lymphoma with 17pdeletion, Waldenström's macroglobulinemia, marginal zone lymphoma whorequire systemic therapy and have received at least one prioranti-CD20-based therapy, unresectable or metastatic melanoma with a BRAFV600E or V600K mutation, allergies, and transplantation.

In some embodiments, the CYP3A4 substrate drug can be indicated for thetreatment of schizophrenia in adults and adolescents (13 to 17 years),depressive episodes associated with Bipolar I Disorder (bipolardepression) in adults, as monotherapy or as adjunctive therapy withlithium or valproate.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of chronic angina.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of cystic fibrosis, e.g., in patients 6 years and older whoare homozygous for the F508del mutation in the CFTR gene.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of chronic lymphocytic leukemia, e.g., in patients with 17pdeletion, who have received at least one prior therapy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of unresectable or metastatic liposarcoma or leiomyosarcoma,e.g., in patients who received a prior anthracycline-containing regimen.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of advanced or metastatic breast cancer, e.g., inpostmenopausal women with hormone receptor (HR)-positive, humanepidermal growth factor receptor 2 (HER2)-negative advanced ormetastatic breast cancer. In a further embodiment, the CYP3A4 substratedrug can be indicated for a treatment of negative advanced or metastaticbreast cancer in postmenopausal women e.g., in combination with anaromatase inhibitor as initial endocrine-based therapy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of Duchenne muscular dystrophy (DMD).

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of secondary hyperparathyroidism (HPT), e.g., in patients withchronic kidney disease (CKD) on dialysis. In one embodiment, the CYP3A4substrate drug can be indicated for the treatment of hypercalcemia,e.g., in patients with parathyroid carcinoma. In one embodiment, theCYP3A4 substrate drug can be indicated for the treatment ofhypercalcemia, e.g., in patients with primary HPT for whoparathyroidectomy would be indicated on the basis of serum calciumlevels, but who are unable to undergo parathyroidectomy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of hallucinations and delusions associated with Parkinson'sdisease psychosis.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of schizophrenia.

In one embodiment, the CYP3A4 substrate drug can be indicated for theacute treatment of manic or mixed episodes associated with bipolar Idisorder.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of chronic hepatitis C (CHC) infection, e. g., as a componentof a combination antiviral treatment regimen with peginterferon alfa andribavirin in HCV genotype 1 infected subjects with compensated liverdisease.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of postmenopausal women with advanced hormonereceptor-positive, HER2-negative breast cancer (advanced HR+BC), e.g.,in combination with exemestane after failure of treatment with letrozoleor anastrozole. In one embodiment, the CYP3A4 substrate drug can beindicated for the treatment of patients with progressive neuroendocrinetumors of pancreatic origin (PNET). In one embodiment, the CYP3A4substrate drug can be indicated for the treatment of patients withprogressive, well-differentiated, non-functional neuroendocrine tumors(NET) of gastrointestinal (GI) or lung origin that are unresectable,locally advanced or metastatic. In one embodiment, the CYP3A4 substratedrug can be indicated for the treatment of patients with advanced renalcell carcinoma (RCC), e.g., after failure of treatment with sunitinib orsorafenib. In one embodiment, the CYP3A4 substrate drug can be indicatedfor the treatment of patients with renal angiomyolipoma and tuberoussclerosis complex (TSC), not requiring immediate surgery. In oneembodiment, the CYP3A4 substrate drug can be indicated for the treatmentof patients with TSC who have subependymal giant cell astrocytoma (SEGA)that require therapeutic intervention but are not candidates forsurgical resection.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of type 2 diabetes mellitus, e.g., as an adjunct to diet andexercise to improve glycemic control in adults.

In one embodiment, the CYP3A4 substrate drug can be indicated to reducethe rate of thrombotic cardiovascular events (e.g., cardiovasculardeath, myocardial infarction, or stroke) in patients with acute coronarysyndrome (ACS).

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of major depressive disorder (MDD).

In one embodiment, the CYP3A4 substrate drug can be indicated to reducethe risk of stroke and systemic embolism in patients with nonvalvularatrial fibrillation. In one embodiment, the CYP3A4 substrate drug can beindicated for the prophylaxis of deep vein thrombosis (DVT), which maylead to pulmonary embolism (PE), e.g., in patients who have undergonehip or knee replacement surgery. In one embodiment, the CYP3A4 substratedrug can be indicated for the treatment of DVT or PE. In one embodiment,the CYP3A4 substrate drug can be indicated to reduce the risk ofrecurrent DVT and PE following initial therapy.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of moderate to severe active rheumatoid arthritis, e.g., inpatients who have had inadequate response or tolerance to methotrexate.

In one embodiment, the CYP3A4 substrate drug can be indicated for theacute treatment of migraine with or without aura.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of chronic phase and accelerated phase Philadelphia chromosomepositive chronic myeloid leukemia (Ph+CML), e.g., in newly diagnosedpatients or in patients resistant to or intolerant to prior therapy thatincluded imatinib.

In one embodiment, the CYP3A4 substrate drug can be indicated to reducethe risk of hospitalization for atrial fibrillation (AF), e.g., inpatients with a history of paroxysmal or persistent AF or atrial flutter(AFK), who are in sinus rhythm or will be cardioverted.

In one embodiment, the CYP3A4 substrate drug can be indicated formaintenance treatment of asthma, e.g., in patients aged 4 years andolder. In one embodiment, the CYP3A4 substrate drug can be indicated formaintenance treatment of airflow obstruction and reducing exacerbationsin patients with chronic obstructive pulmonary disease.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of erectile dysfunction (ED). In one embodiment, the CYP3A4substrate drug can be indicated for the treatment of benign prostatichyperplasia (BPH). In one embodiment, the CYP3A4 substrate drug can beindicated for treatment of pulmonary arterial hypertension (PAH) (WHOGroup 1) to improve exercise ability.

In one embodiment, the CYP3A4 substrate drug can be indicated for thetreatment of gout flares. In one embodiment, the CYP3A4 substrate drugcan be indicated for the treatment of Familial Mediterranean fever.

In one embodiment, the CYP3A4 substrate drug can be indicated for mantlecell lymphoma in patients who have received at least one prior therapy.In one embodiment, the CYP3A4 substrate drug can be indicated forchronic lymphocytic leukemia/small lymphocytic lymphoma In oneembodiment, the CYP3A4 substrate drug can be indicated for chroniclymphocytic leukemia/small lymphocytic lymphoma with 17p deletion.

In one embodiment, the CYP3A4 substrate drug can be indicated forWaldenström's macroglobulinemia.

In one embodiment, the CYP3A4 substrate drug can be indicated formarginal zone lymphoma who require systemic therapy and have received atleast one prior anti-CD20-based therapy.

In one embodiment, the CYP3A4 substrate drug can be indicated forunresectable or metastatic melanoma with a BRAF V600E or V600K mutation.

Other non-limiting examples of conditions or diseases for which CYP3A4substrate drugs are prescribed include antiretroviral therapy, e.g., forthe treatment of HIV/AIDS, anxiety disorders, panic disorders, seizures,insomnia, hypertension, cardiovascular disease (e.g., myocardialinfarction, stroke, and angina), hyperlipidemia, cancer, such as primarykidney cancer, advanced primary liver cancer, radioactive iodineresistant advanced thyroid carcinoma, renal cell carcinoma,imatinib-resistant gastrointestinal stromal tumor, allergies, andtransplantation.

As discussed above, after stopping treatment with a strong CYP3A4inhibitor (including but not limited to posaconazole), posaconazoleaccumulates in the body of patients, and reduces or prevents metabolismof CYP3A4 substrate drugs. Thus, patients previously on posaconazolethat are concomitantly treated with CYP3A4 substrate drugs may haveplasma levels of the CYP3A4 substrate drug that exceed the plasma levelsof an otherwise identical patient that was not previously treated withposaconazole. Described herein, in various embodiments, are treatmentregimens for CYP3A4 substrate drugs which are applicable to patients whopreviously received multiple doses of a strong CYP3A4 inhibitor (e.g.,posaconazole) for a period of about 2-21 days after stopping treatmentwith the strong CYP3A4 inhibitor. In some embodiments, the treatmentregimen provides for treating or prescribing a dose which is less thanabout 50% of the reference dose of the CYP3A4 substrate drug for aperiod of about 2-21 days after stopping posaconazole treatment. As usedherein, a dose that is less than 50% of the reference dose of the CYP3A4inhibitor can include any amount from 0% (i.e., no dose) to about 50% ofthe CYP3A4 inhibitor for the period of 2-21 days. Therefore, thetreatment regimen disclosed herein can include, in some embodiments,delaying a first dose of a CYP3A4 substrate drug for about 2-21 daysafter stopping posaconazole treatment, or alternatively, treating with areduced dose of the CYP3A4 substrate drug for about 2-21 days afterstopping posaconazole treatment. The methods described herein can beapplied to any patient that was previously on posaconazole and having anindication amendable to treatment with a CYP3A4 substrate drug,including normal patients (non-obese and normal metabolizers), obesepatients, and poor or intermediate metabolizers, or combinationsthereof.

In some embodiments, between about 2 and about 21 days, e.g., about 2,about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10,about 11, about 12 days, about 13, about 14, about 15, about 16, about17, about 18, about 19, about 20, or about 21 days, inclusive of allranges and subranges therebetween, should elapse between discontinuationof posaconazole (i.e., the last dose in a posaconazole regimen) andinitiation of treatment with a CYP3A4 substrate drug (i.e., the firstdose in a CYP3A4 regimen of any of the CYP3A4 substrate drugs describedherein). In some embodiments, the patient is a “normal” patient (i.e., apatient with “normal” CYP3A4 enzyme function, often termed an “extensivemetabolizer” in the art; and having a normal weight—e.g., a BMI in therange of about 18.5-24.9), and in other embodiments the patient has oneof the physiological characteristics described herein, e.g., isconsidered obese and/or has a level of CYP3A4 enzyme activity termed inthe art as poor or intermediate.

This “delay” or waiting period between ceasing or stopping the treatmentof posaconazole and initiating treatment with a CYP3A4 substrate drugcan equivalently be characterized as the time that elapses betweenstopping treatment of posaconazole and treating with the first dose ofCYP3A4 substrate drug. The skilled artisan will recognize thatadditional doses of the CYP3A4 substrate drug are typically administeredor prescribed subsequently, but the “delay” or “washout” period asdescribed herein is the time that elapses between stopping treatment ofposaconazole and the first dose that initiates treatment with a CYP3A4substrate drug.

In alternative embodiments, rather than delaying the treatment of theCYP3A4 substrate drug, after stopping treatment of posaconazole theCYP3A4 substrate drug is treated or prescribed at a dose which is nomore than about 50% of a reference dose (the dose recommended for thepatient on the FDA-approved label for the CYP3A4 substrate drug),including e.g., no more than about 50%, no more than about 49%, no morethan about 48%, no more than about 47%, no more than about 46%, no morethan about 45%, no more than about 44%, no more than about 43%, no morethan about 42%, no more than about 41%, no more than about 40%, no morethan about 39%, no more than about 38%, no more than about 37%, no morethan about 36%, no more than about 35%, no more than about 34%, no morethan about 33%, no more than about 32%, no more than about 31%, no morethan about 30%, no more than about 29%, no more than about 28%, no morethan about 27%, no more than about 26%, no more than about 25%, no morethan about 24%, no more than about 23%, no more than about 22%, no morethan about 21%, no more than about 20%, no more than about 19%, no morethan about 18%, no more than about 17%, no more than about 16%, no morethan about 15%, no more than about 14%, no more than about 13%, no morethan about 12%, no more than about 11%, or no more than about 10% of thereference dose, inclusive of all ranges and subranges therebetween, forat least about 2-21 days after discontinuation of the posaconazoleregimen, e.g., for about 2, about 3, about 4, about 5, about 6, about 7,about 8, about 9, about 10, about 11, about 12 days, about 13, about 14,about 15, about 16, about 17, about 18, about 19, about 20, or about 21days, inclusive of all ranges and subranges therebetween.

In other alternative embodiments, depending on the CYP3A4 substratedrug, the patient can be treated with or prescribed a CYP3A4 substratedrug at a dose which is less than 100% of a reference dose (the doserecommended for the patient on the FDA-approved label for the CYP3A4substrate drug), including e.g., about 95%, about 90%, about 85%, about80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50%of the reference dose, inclusive of all ranges and subrangestherebetween, for at least about 2-21 days after discontinuation of theposaconazole treatment, e.g., for about 2, about 3, about 4, about 5,about 6, about 7, about 8, about 9, about 10, about 11, about 12 days,about 13, about 14, about 15, about 16, about 17, about 18, about 19,about 20, or about 21 days, inclusive of all ranges and subrangestherebetween.

In addition to providing methods of treating or prescribing treatmentfor “normal” patients (e.g., non-obese and normal CYP3A4 metabolizers),the present disclosure also provides methods for treating, orprescribing treatment for, patients with at least one of thephysiological characteristics described herein, who had been treatedwith multiple doses of posaconazole, with a CYP3A4 substrate drug. Thetreatment with the CYP3A4 substrate drug is initiated or prescribed tobe initiated (or the first dosing begins after stopping treatment withposaconazole) after a delay time as described herein, or is treated orprescribed at a reduced dose (e.g., any amount less than 100% of areference dose, including but not limited to about ⅓, about ½, about ⅔,etc. of a reference dose) for a time period after treatment withposaconazole is stopped as described herein. The physiologicalcharacteristics of such patients include reduced hepatic enzymefunction, specifically reduced CYP3A4 enzyme function (such patients arecharacterized in the art as intermediate or poor CYP3A4 metabolizers),and/or a weight or body fat status variously characterized as describedherein. In some embodiments, the patients can have variouscharacteristics of body fat status. The term “body fat status,” “bodyfat characteristics,” “obese status,” “obese characteristics,” or otherderivations or variations thereof refer to at least sevencharacteristics (BMI, % IBW, waist size, % body fat, % android fat, %gynoid fat, and total body fat) as described herein. In someembodiments, the body fat status may be referred to as obesity, and thepatients may be referred to as obese, or obese patients.

As described herein, the present Applicants have found that certainclasses of patients, i.e., patients having the particular physiologicalcharacteristics described herein such as body fat and weight statusand/or hepatic metabolizing enzyme status, after stopping treatment withposaconazole, may have substantially higher plasma levels ofposaconazole, and/or exhibit substantially longer elimination half-lives(t_(1/2)) of posaconazole than previously known or contemplated, e.g.,in the NOXAFIL® label, and therefore require either a delay as describedherein after stopping posaconazole treatment, before treating, orprescribing a first treatment to begin, with a CYP3A4 substrate drug, ora dose adjustment (reduction) of the CYP3A4 substrate drug for a timeperiod after stopping posaconazole treatment, as described herein. Insome embodiments, the duration of the delay period or dose adjustmentperiod, or the degree of dose adjustment is greater than thecorresponding delay or dose reduction period/amount compared to thoseconsidered to be “normal” patients. These classes of patients whichexhibit substantially higher plasma levels of posaconazole, and/orexhibit substantially longer elimination half-lives (t_(1/2)) ofposaconazole compared to the expected level (e.g., as embodied in therecommendations of the NOXAFIL® label), or who require a longer delaytime, dose adjustment time, or dose adjustment level include obesepatients who exhibit one or more of e.g., a BMI of at least about 35, %IBW of at least about 150%, waist size greater than about 42 inches, %body fat greater than about 40%, % android body fat greater than about40%, % gynoid body fat greater than about 40%, total body fat greaterthan about 40 kg, optionally in combination with impaired hepaticfunction, e.g., intermediate or poor CYP3A4 metabolizers. Alternatively,patients who are not obese (e.g., have any of the various measures ofbody fat status described herein which are not considered as indicativeof obesity, such as a BMI less than about 35, % IBW of less than about150%, waist size less than about 42 inches, % body fat less than about40%, % android body fat less than about 40%, % gynoid body fat less thanabout 40%, or total body fat less than about 40 kg) but have impairedhepatic metabolic function, e.g., are considered intermediate or poorCYP3A4 metabolizers, have also been found by the present Applicants tohave substantially higher steady state plasma levels of posaconazole,and/or exhibit a substantially longer elimination half-lives (t_(1/2))of posaconazole compared to those expected in “normal” patients—i.e.,patients who do not exhibit the specific physiological characteristicsdescribed herein—or as embodied in the recommendations of the NOXAFIL®label may also require an extended washout period (as described herein)after stopping administration of posaconazole before beginning treatmentwith a CYP3A4 substrate drug. Alternatively, such patients may requirean extended period (as described herein) after stopping administrationof posaconazole before beginning treatment with a reduced dose (asdescribed herein) relative to the reference dose of the CYP3A4 substratedrug in order to minimize or avoid adverse effects such as QTcprolongation or other side effects of the CYP3A4 substrate drug than hashitherto been recognized in the art. Conventionally, no such distinctionbetween patients having such physiological characteristics has beenrecognized as requiring increased “washout” periods between dosing withposaconazole and a CYP3A4 substrate drug, or as requiring time periodsduring which a patient is treated, or prescribed to be treated, with areduced reference dose of the CYP3A4 substrate drug after stoppingadministration of posaconazole, as the effects of such physiologicalcharacteristics on steady state plasma levels of posaconazole and/orelimination half-life was not previously known.

Posaconazole can be metabolized primarily through oxidation viaCytochrome P450 isozymes, in particular CYP3A4. Studies indicate thatother CYP isozymes, such as A2, 2C8, 2C9, 2D6 and 2E1, are not involvedin the metabolism of posaconazole. Each individual may have differentactivity levels of the P450 isozymes that metabolize posaconazole.Categorizations of metabolizers may include, but are not limited to,allelic heterogeneity in the P540 isozymes gene. For instance, theCYP3A4 gene can have allelic heterogeneity and expression of CYP3A4*22allele can be used to classify individuals as reduced-expressers ofCYP3A4 (i.e., individuals possessing one CYP3A4*22 allele), andnormal-expressers of CYP3A4 (i.e., individuals not possessing anyCYP3A4*22 allele).

In some embodiments, the class of patients treated by the methods of thepresent disclosure have a body mass index (BMI; expressed in units ofkg/m² unless otherwise specified) of less than about 25, e.g., about24.5, about 24, about 23.5, about 23, about 22.5, about 22, about 21.5,about 21, about 20.5, about 20, about 19.5, about 19, or about 18.5 orless, inclusive of all values and ranges therebetween.

In some embodiments, the class of patients treated by the methods of thepresent disclosure have a body mass index (BMI; expressed in units ofkg/m² unless otherwise specified) of at least about 25, at least about26, at least about 27, at least about 28, at least about 29, at leastabout 30, at least about 31, at least about 32, at least about 33, atleast about 34, at least about 35, at least about 36, at least about 37,at least about 38, at least about 39, at least about 40, at least about41, at least about 42, at least about 43, at least about 44, at leastabout 45, at least about 46, at least about 47, at least about 48, atleast about 49, at least about 50, at least about 51, at least about 52,at least about 53, at least about 54, at least about 55, at least about56, at least about 57, at least about 58, at least about 59, at leastabout 60, at least about 61, at least about 62, at least about 63, atleast about 64, at least about 65, at least about 66, at least about 67,at least about 68, at least about 69, at least about 70, at least about71, at least about 72, at least about 73, at least about 74, at leastabout 75, at least about 76, at least about 77, at least about 78, atleast about 79, at least about 80, at least about 81, at least about 82,at least about 83, at least about 84, at least about 85, at least about86, at least about 87, at least about 88, at least about 89, at leastabout 90, at least about 91, at least about 92, at least about 93, atleast about 94, at least about 95, at least about 96, at least about 97,at least about 98, at least about 99, at least about 100, at least about101, at least about 102, at least about 103, at least about 104, atleast about 105, at least about 106, at least about 107, at least about108, at least about 109, at least about 110, at least about 111, atleast about 112, at least about 113, at least about 114, at least about115, at least about 116, at least about 117, at least about 118, atleast about 119, at least about 120, at least about 121, at least about122, at least about 123, at least about 124, at least about 125, atleast about 126, at least about 127, at least about 128, at least about129, at least about 130, at least about 131, at least about 132, atleast about 133, at least about 134, at least about 135, at least about136, at least about 137, at least about 138, at least about 139, atleast about 140, at least about 141, at least about 142, at least about143, at least about 144, at least about 145, at least about 146, atleast about 147, at least about 148, at least about 149, at least about150, at least about 151, at least about 152, at least about 153, atleast about 154, at least about 155, at least about 156, at least about157, at least about 158, at least about 159, at least about 160, atleast about 161, at least about 162, at least about 163, at least about164, at least about 165, at least about 166, at least about 167, atleast about 168, at least about 169, at least about 170, at least about171, at least about 172, at least about 173, at least about 174, atleast about 175, at least about 176, at least about 177, at least about178, at least about 179, at least about 180, at least about 181, atleast about 182, at least about 183, at least about 184, at least about185, at least about 186, at least about 187, at least about 188, atleast about 189, at least about 190, at least about 191, at least about192, at least about 193, at least about 194, at least about 195, atleast about 195, at least about 196, at least about 197, at least about198, at least about 199, at least about 200, at least about 201, atleast about 202, at least about 203, at least about 204, at least about205, at least about 206, at least about 207, at least about 208, atleast about 209, or at least about 210, inclusive of all ranges andsubranges therebetween, and any BMI described herein. In one embodiment,the patient has a body mass index (BMI) of at least about 35. In anotherembodiment, the patient has a body mass index (BMI) of at least about40. In another embodiment, the patient has a body mass index (BMI) of atleast 50.

In some embodiments, a patient treated according to the methods of thepresent invention has a BMI of at least about 25 to at least about 29.9,at least about 25.5 to at least about 29, at least about 26 to at leastabout 28.5, at least about 26.5 to at least about 28, or at least about27 to at least about 27.5, inclusive of all ranges and subrangestherebetween, and can be termed overweight or pre-obese. In someembodiments, a patient with a BMI of at least about 30 to at least about34.9, at least about 30.5 to at least about 34, at least about 31 to atleast about 33.5, at least about 31.5 to at least about 33, or at leastabout 32 to at least about 32.5, inclusive of all ranges and subrangestherebetween can be considered obese. In some embodiments, a patientwith a BMI of at least about 35 to at least about 39.9, at least about35.5 to at least about 39, at least about 36 to at least about 38.5, atleast about 36.5 to at least about 38, or at least about 37 to at leastabout 37.5, inclusive of all ranges and subranges therebetween, and anyBMI described herein, can be considered obese. In other embodiments, apatient treated by the methods of the present disclosure has a BMI of atleast about 35 or more, 40 or more, 50 or more, 60 or more, 70 or more,80 or more, 90 or more, 100 or more, 110 or more, 120 or more, 130 ormore, 140 or more, 150 or more, 160 or more, 170 or more, 180 or more,190 or more, 200 or more, or 210 or more, inclusive of all ranges andsubranges therebetween.

In some embodiments, the patient treated according to the methods of thepresent disclosure is a child or an adolescent with a BMI of at leastabout the 85^(th) percentile to at least about 95^(th) percentile, atleast about the 86^(th) percentile to at least about 94^(th) percentile,at least about the 87^(th) percentile to at least about 93^(th)percentile, at least about the 88^(th) percentile to at least about92^(th) percentile, at least about the 89^(th) percentile to at leastabout 90^(th) percentile, inclusive of all ranges and subrangestherebetween, can be considered overweight or pre-obese. In someembodiments, the patient is a patient with a BMI of at least about the95^(th) percentile, at least about 96^(th) percentile, at least aboutthe 97^(th) percentile, at least about 98^(th) percentile, at leastabout 99^(th) percentile, or at least about 100^(th) percentile,inclusive of all ranges and subranges therebetween, and any BMIpercentile described herein, and can be considered obese. In oneembodiment, the patient is about 5 to about 19 years old or about 7 toabout 18 years old.

In some embodiments, the patient treated according to the methods of thepresent disclosure is a female patient in the first trimester throughthird trimester of a pregnancy and has a BMI of at least 25 to at leastabout 29.9, at least about 25.5 to at least about 29, at least about 26to at least about 28.5, at least about 26.5 to at least about 28, or atleast about 27 to at least about 27.5, inclusive of all ranges andsubranges therebetween, and can be considered overweight or pre-obese.In some embodiments, the patient is a female patient in the firsttrimester through third trimester of a pregnancy and has a BMI of atleast about 30 to at least about 34.9, at least about 30.5 to at leastabout 34, at least about 31 to at least about 33.5, at least about 31.5to at least about 33, or at least about 32 to at least about 32.5,inclusive of all ranges and subranges therebetween, and can beconsidered obese. In some embodiments, the patent treated according tothe methods of the present invention is a female patient in the firsttrimester through third trimester of a pregnancy and has a BMI of atleast about 35 to at least about 39.9, at least about 35.5 to at leastabout 39, at least about 36 to at least about 38.5, at least about 36.5to at least about 38, at least about 37 to at least about 37.5,inclusive of all ranges and subranges therebetween, and can beconsidered severely obese.

In some embodiments, methods of calculating BMI may include, but are notlimited to body weight in kilogram/(height in meters)², body weight inpounds/(height in inches)²]×703, and the like.

In some embodiments, the patient treated according to the methods of thepresent disclosure can alternatively be described as having a % idealbody weight (% IBW) of at least about 110%, at least about 111%, atleast about 112%, at least about 113%, at least about 114%, at leastabout 115%, at least about 116%, at least about 117%, at least about118%, at least about 119%, at least about 120%, at least about 121%, atleast about 122%, at least about 123%, at least about 124%, at leastabout 125%, at least about 126%, at least about 127%, at least about128%, at least about 129%, at least about 130%, at least about 131%, atleast about 132%, at least about 133%, at least about 134%, at leastabout 135%, at least about 136%, at least about 137%, at least about138%, at least about 139%, at least about 140%, at least about 141%, atleast about 142%, at least about 143%, at least about 144%, at leastabout 145%, at least about 146%, at least about 147%, at least about148%, at least about 149%, at least about 150%, at least about 151%, atleast about 152%, at least about 153%, at least about 154%, at leastabout 155%, at least about 156%, at least about 157%, at least about158%, at least about 159%, at least about 160%, at least about 161%, atleast about 162%, at least about 163%, at least about 164%, at leastabout 165%, at least about 166%, at least about 167%, at least about168%, at least about 169%, at least about 170%, at least about 171%, atleast about 172%, at least about 173%, at least about 174%, at leastabout 175%, at least about 176%, at least about 177%, at least about178%, at least about 179%, at least about 180%, at least about 181%, atleast about 182%, at least about 183%, at least about 184%, at leastabout 185%, at least about 186%, at least about 187%, at least about188%, at least about 189%, at least about 190%, at least about 191%, atleast about 192%, at least about 193%, at least about 194%, at leastabout 195%, at least about 196%, at least about 197%, at least about198%, at least about 199%, at least about 200%, at least about 201%, atleast about 202%, at least about 203%, at least about 204%, at leastabout 205%, at least about 206%, at least about 207%, at least about208%, at least about 209%, at least about 210%, at least about 211%, atleast about 212%, at least about 213%, at least about 214%, at leastabout 215%, at least about 216%, at least about 217%, at least about218%, at least about 219%, at least about 220%, at least about 221%, atleast about 222%, at least about 223%, at least about 224%, at leastabout 225%, at least about 226%, at least about 227%, at least about228%, at least about 229%, at least about 230%, at least about 231%, atleast about 232%, at least about 233%, at least about 234%, at leastabout 235%, at least about 236%, at least about 237%, at least about238%, at least about 239%, at least about 240%, at least about 241%, atleast about 242%, at least about 243%, at least about 244%, at leastabout 245%, at least about 246%, at least about 247%, at least about248%, at least about 249%, at least about 250%, at least about 251%, atleast about 252%, at least about 253%, at least about 254%, at leastabout 255%, at least about 256%, at least about 257%, at least about258%, at least about 259%, at least about 260%, at least about 261%, atleast about 262%, at least about 263%, at least about 264%, at leastabout 265%, at least about 266%, at least about 267%, at least about268%, at least about 269%, at least about 270%, at least about 271%, atleast about 272%, at least about 273%, at least about 274%, at leastabout 275%, at least about 276%, at least about 277%, at least about278%, at least about 279%, or at least about 280%, inclusive of allranges and subranges therebetween, and any % ideal body weight describedherein. In one embodiment, the patient has % ideal body weight (IBW) ofat least about 150%. In one embodiment, the patient has % ideal bodyweight (IBW) of at least about 250%. In other embodiment, the patienthas % IBW of at least 150% and can be considered obese.

In some embodiments, the patient treated according to the presentdisclosure can alternatively be described as having a waist size orwaist circumference greater than about 32, greater than about 33,greater than about 34, greater than about 35 inches, greater than about36, greater than about 37, greater than about 38, greater than about 39,greater than about 40, greater than about 41, greater than about 42,greater than about 43, greater than about 44, greater than about 45,greater than about 46, greater than about 47, greater than about 48,greater than about 49, greater than about 50, greater than about 51,greater than about 52, greater than about 53, greater than about 54,greater than about 55, greater than about 56, greater than about 57,greater than about 58, greater than about 59, greater than about 60inches, greater than about 61 inches, greater than about 62 inches,greater than about 63 inches, greater than about 64 inches, greater thanabout 65 inches, inclusive of all ranges and subranges therebetween, andany waist size or circumference described herein. In one embodiment, apatient having a waist size or waist circumference of about 42 inchescan be considered obese. In another embodiment, the patient has waistsize or waist circumference greater than about 48 inches. In otherembodiment, the patient has waist or waist circumference of at least 42inches.

In some embodiments, the patient treated according to the methods of thepresent disclosure can alternatively be described as having a % body fatgreater than about 20%, greater than about 21%, greater than about 22%,greater than about 23%, greater than about 24%, greater than about 25%,greater than about 26%, greater than about 27%, greater than about 28%,greater than about 29%, greater than about 30%, greater than about 31%,greater than about 32%, greater than about 33%, greater than about 34%,greater than about 35%, greater than about 36%, greater than about 37%,greater than about 38%, greater than about 39%, greater than about 40%,greater than about 41%, greater than about 42%, greater than about 43%,greater than about 44%, greater than about 45%, greater than about 46%,greater than about 47%, greater than about 48%, greater than about 49%,or greater than about 50%, inclusive of all ranges and subrangestherebetween, and any % body fat described herein. In one embodiment,the patient has a % body fat greater than about 40%. In one embodiment,the patient has a % body fat of at least about 50%. In anotherembodiment, a patient having a % body fat greater than about 40% can beconsidered obese. In some embodiments, methods of calculating % body fatcan include, but are not limited to total body fat expressed as apercentage of total body weight. Other standards for obesity can beused. For example, the American Council on Exercise suggests that an“average” percentage of body fat for women is about 25-31%, and for men,about 18-24%, and for obese women, about 32% and higher, and obese men,about 25% and higher.

In other embodiments, the patient can alternatively be described ashaving a % android body fat greater than about 30%, greater than about31%, greater than about 32%, greater than about 33%, greater than about34%, greater than about 35%, greater than about 36%, greater than about37%, greater than about 38%, greater than about 39%, greater than about40%, greater than about 41%, greater than about 42%, greater than about43%, greater than about 44%, greater than about 45%, greater than about46%, greater than about 47%, greater than about 48%, greater than about49%, greater than about 50%, greater than about 51%, greater than about52%, greater than about 53%, greater than about 54%, greater than about55%, greater than about 56%, greater than about 57%, greater than about58%, greater than about 59%, greater than about 60%, greater than about61%, greater than about 62%, greater than about 63%, greater than about64%, greater than about 65%, greater than about 66%, greater than about67%, greater than about 68%, greater than about 69%, greater than about70%, greater than about 71%, greater than about 72%, greater than about73%, greater than about 74%, greater than about 75%, greater than about76%, greater than about 77%, greater than about 78%, greater than about79%, or greater than about 80%, inclusive of all ranges and subrangestherebetween, and any % android body fat described herein. In oneembodiment, a patient having a % android body fat greater than about 40%can be considered obese. In one embodiment, a patient having a % androidbody fat greater than about 50% can be considered obese

In other embodiments, the patient can alternatively be described ashaving a % android body fat of at least about 30%, at least about 31%,at least about 32%, at least about 33%, at least about 34%, at leastabout 35%, at least about 36%, at least about 37%, at least about 38%,at least about 39%, at least about 40%, at least about 41%, at leastabout 42%, at least about 43%, at least about 44%, at least about 45%,at least about 46%, at least about 47%, at least about 48%, at leastabout 49%, at least about 50%, at least about 51%, at least about 52%,at least about 53%, at least about 54%, at least about 55%, at leastabout 56%, at least about 57%, at least about 58%, at least about 59%,at least about 60%, at least about 61%, at least about 62%, at leastabout 63%, at least about 64%, at least about 65%, at least about 66%,at least about 67%, at least about 68%, at least about 69%, at leastabout 70%, at least about 71%, at least about 72%, at least about 73%,at least about 74%, at least about 75%, at least about 76%, at leastabout 77%, at least about 78%, at least about 79%, or at least about80%, inclusive of all ranges and subranges therebetween, and % androidbody fat described herein. In one embodiment, the patient has % androidbody fat of at least about 50%.

In other embodiments, the patient can alternatively be described ashaving a % gynoid body fat greater than about 30%, greater than about31%, greater than about 32%, greater than about 33%, greater than about34%, greater than about 35%, greater than about 36%, greater than about37%, greater than about 38%, greater than about 39%, greater than about40%, greater than about 41%, greater than about 42%, greater than about43%, greater than about 44%, greater than about 45%, greater than about46%, greater than about 47%, greater than about 48%, greater than about49%, greater than about 50%, greater than about 51%, greater than about52%, greater than about 53%, greater than about 54%, greater than about55%, greater than about 56%, greater than about 57%, greater than about58%, greater than about 59%, greater than about 60%, greater than about61%, greater than about 62%, greater than about 63%, greater than about64%, greater than about 65%, greater than about 66%, greater than about67%, greater than about 68%, greater than about 69%, greater than about70%, greater than about 71%, greater than about 72%, greater than about73%, greater than about 74%, greater than about 75%, greater than about76%, greater than about 77%, greater than about 78%, greater than about79%, or greater than about 80%, inclusive of all ranges and subrangestherebetween, and any % gynoid body fat described herein. In oneembodiment, a patient having a % gynoid body fat greater than about 40%can be considered obese. In one embodiment, a patient having a % gynoidbody fat greater than about 50% can be considered obese.

In other embodiments, the patient can alternatively be described ashaving a total body fat content greater than about 30 kg, greater thanabout 31 kg, greater than about 32 kg, greater than about 33 kg, greaterthan about 34 kg, greater than about 35 kg, greater than about 36 kg,greater than about 37 kg, greater than about 38 kg, greater than about39 kg, greater than about 40 kg, greater than about 41 kg, greater thanabout 42 kg, greater than about 43 kg, greater than about 44 kg, greaterthan about 45 kg, greater than about 46 kg, greater than about 47 kg,greater than about 48 kg, greater than about 49 kg, greater than about50 kg, greater than about 51 kg, greater than about 52 kg, greater thanabout 53 kg, greater than about 54 kg, greater than about 55 kg, greaterthan about 56 kg, greater than about 57 kg, greater than about 58 kg,greater than about 59 kg, greater than about 60 kg, greater than about61 kg, greater than about 62 kg, greater than about 63 kg, greater thanabout 64 kg, greater than about 65 kg, greater than about 66 kg, greaterthan about 67 kg, greater than about 68 kg, greater than about 69 kg,greater than about 70 kg, greater than about 71 kg, greater than about72 kg, greater than about 73 kg, greater than about 74 kg, greater thanabout 75 kg, greater than about 76 kg, greater than about 77 kg, greaterthan about 78 kg, greater than about 79 kg, greater than about 80 kg,greater than about 81 kg, greater than about 82 kg, greater than about83 kg, greater than about 84 kg, greater than about 85 kg, greater thanabout 86 kg, greater than about 87 kg, greater than about 88 kg, greaterthan about 89 kg, greater than about 90 kg, greater than about 91 kg,greater than about 92 kg, greater than about 93 kg, greater than about94 kg, greater than about 95 kg, greater than about 96 kg, greater thanabout 97 kg, greater than about 98 kg, greater than about 99 kg, greaterthan about 100 kg, at least 101 kg, at least 102 kg, at least 103 kg, atleast 104 kg, at least 105 kg, at least 106 kg, at least 107 kg, atleast 108 kg, at least 109 kg, or at least 110 kg, inclusive of allranges and subranges therebetween, and any total body fat describedherein. In one embodiment, a patient having total body fat greater thanabout 40 kg can be considered obese. In one embodiment, a patient havingtotal body fat greater than about 50 kg can be considered obese.

In other embodiments, the obesity status of patients treated with themethods of the present disclosure can be measured by waist-to-hip ratio.In other embodiments, the obesity status of patients can be measured byskinfold thickness. In other embodiments, the obesity status of patientscan be measured by bioelectric impedance. In other embodiments, theobesity status of patients can be measured by underwater weighing ordensitometry. In other embodiments, the obesity status of patients canbe measured by air-displacement plethysmography. In other embodiments,the obesity status of patients can be measured by dilution method orhydrometry. In other embodiments, the obesity status of patients can bemeasured by dual energy X-ray absorptiometry. In other embodiments, theobesity status of patients can be measured by computerized tomographyand magnetic resonance imaging. In some embodiments, the obesity statuscan be defined by, but is not limited to adopting the clinicalstandards, conventional standards, and/or the standards published by theWorld Health Organization and Center of Disease Control (both of whichare herein incorporated by reference in their entireties for allpurposes) when using the methods described herein. For example, the WHOdefines an obese person as a person with a BMI of 30 or more, anoverweight person is one with a BMI equal to or more than 25 (to lessthan 30). Similarly, the CDC defines normal as a BMI of 18.5 to lessthan 25, 25.0 to less than 30 as overweight, and 30.0 or higher asobese. The CDC further subdivides obesity into 3 classes: Class 1, a BMIof 30 to less than 35; Class 2, a BMI of 35 to less than 40; and Class3, as a BMI of 40 or higher. The CDC sometimes refers to Class 3 obesityas “extreme” or “severe” obesity.

In some embodiments, the patient treated by the methods of the presentdisclosure can be characterized by two or more of the physiologicalcharacteristics described herein. For example the patient can have a BMIof at least about 35 and can have a % IBW of at least 150%. In someembodiments, the patient can have a BMI of at least about 35 and canhave a waist size greater than about 42 inches. In some embodiments, thepatient can have a BMI of at least about 35 and can have a % body fatgreater than about 40%. In some embodiments, the patient can have a BMIof at least about 35 and can have a % android body fat greater thanabout 40%. In some embodiments, the patient can have a BMI of at leastabout 35 and can have a % gynoid body fat greater than about 40%. Insome embodiments, the patient can have a BMI of at least about 35 andcan have total body fat greater than about 40 kg. In various otherembodiments, the patient can have any combination of two or more of anyof the specific physiological parameters described herein.

In some embodiments, the patient can have three or more of thephysiological parameters described herein, for example a BMI of at leastabout 35, a % IBW of at least 150%, and waist size greater than about 42inches. In some embodiments, the patient can have a BMI of at leastabout 35, a % IBW of at least 150%, and a % body fat greater than about40%. In some embodiments, the patient can have a BMI of at least about35, a % IBW of at least 150%, and a android body fat greater than about40%. In some embodiments, the patient can have a BMI of at least about35, a % IBW of at least 150%, and a % gynoid body fat greater than about40%. In some embodiments, the patient can have a BMI of at least about35, a % IBW of at least 150%, and total body fat greater than about 40kg. In various other embodiments, the patient can have any combinationof three or more of any of the specific physiological parametersdescribed herein.

In some embodiments, the patient can have four or more of thephysiological parameters described herein, for example the patient canhave a BMI of at least about 35, a % IBW of at least 150%, waist sizegreater than about 42 inches, and a % body fat greater than about 40%.In some embodiments, the patient can have a BMI of at least about 35, a% IBW of at least 150%, waist size greater than about 42 inches, and a %android body fat greater than about 40%. In some embodiments, thepatient can have a BMI of at least about 35, a % IBW of at least 150%,waist size greater than about 42 inches, and a % gynoid body fat greaterthan about 40%. In some embodiments, the patient can have a BMI of atleast about 35, a % IBW of at least 150%, a waist size greater thanabout 42 inches, and total body fat greater than about 43 kg. In some aembodiments, the patient can have a BMI of at least about 35, a % IBW ofat least 150%, a waist size greater than about 42 inches, a % body fatgreater than about 40%, and a % android body fat greater than about 40%.In some embodiments, the patient can have a BMI of at least about 35, a% IBW of at least 150%, a waist size greater than about 42 inches, a %body fat greater than about 40%, and a % gynoid body fat greater thanabout 40%. In some embodiments, the patient can have a BMI of at leastabout 35, a % IBW of at least 150%, a waist size greater than about 42inches, a % body fat greater than about 40%, and total body fat greaterthan about 40 kg. In some embodiments, the patient can have a BMI of atleast about 35, a % IBW of at least 150%, a waist size greater thanabout 42 inches, a % body fat greater than about 40%, a % android bodyfat greater than about 40%, in % gynoid body fat greater than about 40%,and total body fat greater than about 40 kg. In one embodiment, thepatient who has a BMI of at least about 35, in % IBW of at least 150%, awaist size greater than about 42 inches, and a % body fat greater thanabout 40%, a % android body fat greater than about 40%, a % gynoid bodyfat greater than about 40%, and total body fat greater than about 40 kg.In various other embodiments, the patient can have any combination ofany or all of the specific physiological parameters described herein.

In some embodiments, the patient can have a waist size greater thanabout 42 inches, a body fat greater than about 40%, and a % android bodyfat greater than about 40%. In some embodiments, the patient can have awaist size greater than about 42 inches, a % body fat greater than about40%, and a % gynoid body fat greater than about 40%. In someembodiments, the patient can have a waist size greater than about 42inches, a % body fat greater than about 40%, and total body fat greaterthan about 40 kg.

In some embodiments, the patient can have a % body fat greater thanabout 40%, a android body fat greater than about 40%, and a % gynoidbody fat greater than about 40%. In some embodiments, the patient canhave a % body fat greater than about 40%, a % android body fat greaterthan about 40%, and total body fat greater than about 40 kg. In someembodiments, the patient can have a % body fat greater than about 40%, a% gynoid body fat greater than about 40%, and total body fat greaterthan about 40 kg. In some embodiments, a % android body fat greater thanabout 40%, and a % gynoid body fat greater than about 40%, and totalbody fat greater than about 43 kg. In some embodiments, the patient canhave any combinations of obesity characteristics described herein

In some embodiments, patients with at least one of the obesitycharacteristics described herein can be an intermediate CYP3A4metabolizer. In other embodiments, the patients with at least one of theobesity characteristics described herein can be a poor CYP3A4metabolizer. In some embodiments, the patients with at least one of theobesity characteristics described herein can be an extensive CYP3A4metabolizer. In still other embodiments, the patient is not obese, e.g.,can have normal weight, and be an intermediate or poor CYP3A4metabolizer.

Alternatively, in some embodiments, the CYP3A4 genotype can be tested byusing targeted variant analysis. In some embodiments, the CYP3A4genotype can be tested by using sequence analysis of select exons.

In various embodiments, the present disclosure also provides for methodsof treating patients previously treated with posaconazole with a CYP3A4substrate drug which is contraindicated for concomitant use with astrong CYP3A4 inhibitor, such as posaconazole, wherein the CYP3A4substrate drug maintains an AUC which is no more than about 450% of anormal baseline AUC (as defined above) of the CYP3A4 substrate drug,e.g., no more than about 445%, no more than about 440%, no more thanabout 435%, no more than 430%, no more than about 425%, no more thanabout 420%, no more than about 415%, no more than about 410%, no morethan about 405%, no more than about 400%, no more than about 395%, nomore than about 390%, no more than about 385%, no more than about 380%,no more than about 375%, no more than about 370%, no more than about365%, no more than about 360%, no more than about 355%, no more thanabout 350%, no more than about 345%, no more than about 340%, no morethan about 335%, no more than 330%, no more than about 325%, no morethan about 320%, no more than about 315%, no more than about 310%, nomore than no more than about 305%, or no more than about 300%, no morethan about 295%, no more than about 290%, no more than about 285%, nomore than about 280%, no more than about 275%, no more than about 270%,no more than about 265%, no more than about 260%, no more than about255%, no more than about 250%, no more than about 245%, no more thanabout 240%, no more than about 235%, no more than 230%, no more thanabout 225%, no more than about 220%, no more than about 216%, no morethan about 215%, no more than about 210%, no more than about 205%, nomore than about 200%, no more than about 195%, no more than about 190%,no more than about 185%, no more than about 180%, no more than about175%, no more than about 170%, no more than about 165%, no more thanabout 160%, no more than about 155%, no more than about 150%, no morethan about 145%, no more than about 140%, no more than about 135%, nomore than 130%, no more than about 125%, no more than about 120%, nomore than about 115%, no more than about 110%, no more than no more thanabout 105%, or no more than about 100% of the normal baseline AUC of theCYP3A4 substrate drug, inclusive of all ranges and subrangestherebetween. In particular embodiments, the CYP3A4 substrate drug isranolazine, and the AUC of ranolazine is maintained at a level of nomore than about 150% of a normal baseline AUC of ranolazine. As usedherein, the “normal baseline AUC of ranolazine” refers to the steadystate AUC₀₋₁₂ measured for a particular dose of ranolazine in theabsence of other drugs. In some embodiments, the steady state AUC₀₋₁₂ (%CV) is 13,720 (67.0%) ng*h/mL measured after administration of 500 mgranolazine. In some embodiments, the steady state AUC₀₋₁₂ (% CV) is32,091 (42.2%) ng*h/mL measured after administration of 1,000 mgranolazine. In other particular embodiments, the CYP3A4 substrate drugis lurasidone, and the AUC of lurasidone is maintained at a level of nomore than about 216% of a normal baseline AUC of lurasidone. As usedherein, the “normal baseline AUC of lurasidone” refers to the meanAUC_(0-tau) measured for a particular dose of lurasidone in the absenceof other drugs. In some embodiments, the mean AUC_(0-tau) is about 743ng*h/mL measured after administration of 120 mg lurasidone administeredin the fed state after a 350 kcal meal. In other particular embodiments,the CYP3A4 drug is tadalafil, and the AUC of tadalafil is maintained ata level of no more than about 410% of a normal baseline AUC oftadalafil. As used herein, the “normal baseline AUC of tadalafil” refersto the mean AUC_(0-∞) (% CV) measured for a particular dose of tadalafilin the absence of other drugs. In some embodiments, the mean AUC_(0-∞)(% CV) is about 3647 (34.0%) μg*h/L measured after administration of 10mg tadalafil. In some embodiments, the mean AUC_(0-∞) (% CV) is about13,006 (43.9%) μg*h/L for 20 mg tadalafil. In some embodiments, the meanAUC_(0-∞) (% CV) is within the range of about 7,000 to about 13,000(40.0%) μg*h/L for 20 mg tadalafil.

In various other embodiments, the present disclosure provides formethods of treating patients previously treated with posaconazole,comprising treating or prescribing a reduced dose of a CYP3A4 substratedrug which is contraindicated for concomitant use with a strong CYP3A4inhibitor (e.g., about 10%-90%, of the reference dose) for a period ofabout 2-21 days after stopping posaconazole treatment as describedherein, wherein the CYP3A4 substrate drug is maintained an AUC which isno more than about 450% of the baseline AUC of the CYP3A4 substratedrug, e.g., no more than about 445%, no more than about 440%, no morethan about 435%, no more than 430%, no more than about 425%, no morethan about 420%, no more than about 415%, no more than about 410%, nomore than about 405%, no more than about 400%, no more than about 395%,no more than about 390%, no more than about 385%, no more than about380%, no more than about 375%, no more than about 370%, no more thanabout 365%, no more than about 360%, no more than about 355%, no morethan about 350%, no more than about 345%, no more than about 340%, nomore than about 335%, no more than 330%, no more than about 325%, nomore than about 320%, no more than about 315%, no more than about 310%,no more than no more than about 305%, or no more than about 300%, nomore than about 295%, no more than about 290%, no more than about 285%,no more than about 280%, no more than about 275%, no more than about270%, no more than about 265%, no more than about 260%, no more thanabout 255%, no more than about 250%, no more than about 245%, no morethan about 240%, no more than about 235%, no more than 230%, no morethan about 225%, no more than about 220%, no more than about 216%, nomore than about 215%, no more than about 210%, no more than about 205%,no more than about 200%, no more than about 195%, no more than about190%, no more than about 185%, no more than about 180%, no more thanabout 175%, no more than about 170%, no more than about 165%, no morethan about 160%, no more than about 155%, no more than about 150%, nomore than about 145%, no more than about 140%, no more than about 135%,no more than 130%, no more than about 125%, no more than about 120%, nomore than about 115%, no more than about 110%, no more than no more thanabout 105%, or no more than about 100% of the normal baseline AUC of theCYP3A4 substrate drug, inclusive of all ranges and subrangestherebetween. In particular embodiments, the CYP3A4 substrate drug isranolazine, and the AUC of ranolazine is maintained at a level of nomore than about 150% of the normal baseline AUC of ranolazine. In otherparticular embodiments, the CYP3A4 substrate drug is lurasidone, and theAUC of lurasidone is maintained at a level of no more than about 216% ofthe normal baseline AUC of lurasidone. In other particular embodiments,the CYP3A4 substrate drug is tadalafil, and the AUC of tadalafil ismaintained at a level of no more than about 410% of the normal baselineAUC of tadalafil. In other particular embodiments, the CYP3A4 substratedrug is tadalafil, and the AUC of tadalafil is maintained at a level ofno more than about 260% of the normal baseline AUC of tadalafil. Inother particular embodiments, the CYP3A4 substrate drug is tadalafil,and the AUC of tadalafil is maintained at a level of no more than about207% of the normal baseline AUC of tadalafil.

In various embodiments, the present disclosure also provides for methodsof treating patients previously treated with posaconazole, with a CYP3A4substrate drug which is contraindicated for concomitant use with astrong CYP3A4 inhibitor, such as posaconazole, wherein the CYP3A4substrate drug maintains a C_(max) which is no more than about 210% ofthe normal baseline C_(max) of the CYP3A4 substrate drug, e.g., no morethan about 210%, no more than about 205%, no more than about 200%, nomore than about 195%, no more than 190%, no more than about 185%, nomore than about 180%, no more than about 175%, no more than about 170%,no more than 165%, no more than about 160%, no more than about 155%, nomore than about 150%, no more than about 145%, no more than about 140%,no more than about 135%, no more than about 130%, no more than about125%, no more than about 120%, no more than about 115%, no more thanabout 110%, no more than about 105%, or no more than about 100%inclusive of all ranges and subranges therebetween. In particularembodiments, the CYP3A4 substrate drug is ranolazine, and the C_(max) ofranolazine is maintained at a level of no more than about 150% of thenormal baseline C_(max) of ranolazine. As used herein, the “normalbaseline C_(max) of ranolazine” refers to the steady state C_(max)measured for a particular dose of ranolazine in the absence of otherdrugs. In some embodiments, the steady state C_(max) (% CV) is 1081(49.1%) ng/mL measured after administration of 500 mg ranolazine. Insome embodiments, the steady state C_(max) (% CV) is 1955 (54.0%) ng/mLmeasured after administration of 1,000 mg ranolazine. In otherparticular embodiments, the CYP3A4 substrate drug is lurasidone, and theC_(max) of lurasidone is maintained at a level of no more than about210% of the normal baseline C_(max) of lurasidone. As used herein, the“normal baseline C_(max) of lurasidone” refers to the mean C_(max)measured for a particular dose of lurasidone in the absence of otherdrugs. In some embodiments, the mean C_(max) (% CV) is about 160 ng/mLmeasured after administration of 120 mg lurasidone in the fed statefollowing a 350 kcal meal. In other particular embodiments, the CYP3A4substrate drug is tadalafil, and the C_(max) of tadalafil is maintainedat a level of no more than about 120% of the normal baseline C_(max) oftadalafil. As used herein, the “normal baseline C_(max) of tadalafil”refers to the mean C_(max) measured for a particular dose of tadalafilin the absence of other drugs. In some embodiments, the mean C_(max) (%CV) is 190 (21.7%) μg/L measured after administration of 10 mgtadalafil. In some embodiments, the mean C_(max) (% CV) is 548 (24.0%)μg/L measured after administration of 20 mg tadalafil.

In various other embodiments, the present disclosure provides formethods of treating patients previously on posaconazole with a reduceddose of a CYP3A4 substrate drug (e.g., about 10%-50% of the referencedose) which is contraindicated for concomitant use with a strong CYP3A4inhibitor, wherein the CYP3A4 substrate drug is maintained at a dosewhich provides a C_(max) which is no more than about 250% of the normalbaseline C_(max) of the CYP3A4 substrate drug for a period of at leastabout 2 to at least about 21 days after stopping posaconazole treatment,e.g., no more than about 250%, no more than about 245%, no more thanabout 240%, no more than about 235%, no more than 230%, no more thanabout 225%, no more than about 220%, no more than about 215%, no morethan about 210%, no more than 205%, no more than about 200%, no morethan about 195%, no more than about 190%, no more than about 185%, nomore than about 180%, no more than about 175%, no more than about 170%,no more than about 165%, no more than about 160%, no more than about155%, no more than about 150%, no more than about 145%, no more thanabout 140%, no more than about 135%, no more than 130%, no more thanabout 125%, no more than about 120%, no more than about 115%, no morethan about 110%, no more than no more than about 105%, or no more thanabout 100% inclusive of all ranges and subranges therebetween. Inparticular embodiments, the CYP3A4 substrate drug is ranolazine, and theC_(max) of ranolazine is maintained at a level of no more than about150% of the normal baseline C_(max) of ranolazine. In other particularembodiments, the CYP3A4 substrate drug is lurasidone, and the C_(max) oflurasidone is maintained at a level of no more than about 210% of thenormal baseline C_(max) of lurasidone. In other particular embodiments,the CYP3A4 substrate drug is tadalafil, and the C_(max) of tadalafil ismaintained at a level of no more than about 120% of the normal baselineC_(max) of tadalafil.

In embodiments in which the CYP3A4 substrate drug is ranolazine, thedaily dose of ranolazine is no more than about 500 mg, e.g., about 490mg, about 480 mg, about 470 mg, out 460 mg, about 450 mg, about 440 mg,about 430 mg, about 420 mg, about 410 mg, about 400 mg, about 390 mg,about 380 mg, about 370 mg, 360 mg, about 350 mg, about 340 mg, about330 mg, about 320 mg, about 310 mg, about 300 mg, about 290 mg, about280 mg, about 270 mg, 260 mg, about 250 mg, about 240 mg, about 230 mg,about 220 mg, about 210 mg, about 100 mg, about 190 mg, about 180 mg,about 170 mg, 160 mg, about 150 mg, about 140 mg, about 130 mg, about120 mg, about 110 mg, about 100 mg, about 90 mg, about 80 mg, about 70mg, about 60 mg, or about 50 mg, inclusive of all values and rangestherebetween, and treatment is delayed for at least about 2-21 daysafter discontinuation of the posaconazole regimen, or reduced for thetime period of about 2-21 days after discontinuation of the posaconazoleregimen.

In embodiments in which the CYP3A4 substrate drug is lurasidone, thedaily dose of lurasidone is no more than about 80 mg, e.g., about 75,about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg,about 15 mg, or about 10 mg, inclusive of all values and rangestherebetween, and treatment is delayed for at least about 2-21 daysafter discontinuation of the posaconazole regimen, or reduced for thetime period of about 2-21 days after discontinuation of the posaconazoleregimen.

In embodiments in which the CYP3A4 substrate drug is tadalafil, thedaily dose of tadalafil is no more than about 2.5 mg, e.g., about 2.25mg, about 2.0 mg, about 1.75 mg, about 1.5 mg, about 1.25 mg, about 1.0mg, about 0.75 mg, or about 0.5 mg, inclusive of all values and rangestherebetween, and treatment is delayed for at least about 2-21 daysafter discontinuation of the posaconazole regimen, or reduced for thetime period of about 2-21 days after discontinuation of the posaconazoleregimen.

In other embodiments in which the CYP3A4 substrate drug is tadalafil,the 72 hr dose of tadalafil is no more than about 10 mg, e.g., about 9.5mg, about 9.0 mg, about 8.5 mg, about 8.0 mg, about 7.5 mg, about 7.0mg, about 6.5 mg, about 6.0 mg, about 5.5 mg, about 5.0 mg, about 4.5mg, about 4.0 mg, about 3.5 mg, about 3.0 mg, about 2.5 mg, about 2.0mg, about 1.5 mg, about 1.0 mg, or about 0.5 mg, inclusive of all valuesand ranges therebetween, and treatment is delayed for at least about2-21 days after discontinuation of the posaconazole regimen, or reducedfor the time period of about 2-21 days after discontinuation of theposaconazole regimen.

In some embodiments, the time period for delaying treatment of theCYP3A4 substrate drug, or the time period during which the patient istreated with a reduced dose (e.g., no more than about 90%, about 75%,about 50%, about 25%, etc. of the reference dose) of the CYP3A4substrate, is at least about 1.5 times the reported average t_(1/2) ofposaconazole, e.g., about 2 times, about 2.5 times, about 3 times, about3.5 times, about 4 times, about 4.5 times, about 5 times, about 5.5times, about 6 times, about 6.5 times, about 7 times, about 7.5 times,about 8 times, about 8.5 times, about 9 times, about 9.5 times, about 10times, inclusive of all values and subranges therebetween.

The present disclosure also provides methods for treating, orprescribing treatment, with a CYP3A4 substrate drug intended to treatany of the disorders or conditions described herein, to a patient whohas been administered posaconazole prior to the administration of theCYP3A4 substrate drug. In addition to treating the disorder or conditiontreatable with the CYP3A4 substrate drug, in some embodiments themethods of the present invention reduce the severity or incidence ofside effects associated with administration of the CYP3A4 substrate drugafter stopping administration of posaconazole. In embodiments, thesemethods include (a) treating a patient with multiple doses ofposaconazole, (b) not administering the CYP3A4 substrate drug during theadministration of the posaconazole regimen, (c) stopping administrationof posaconazole, (d) delaying treatment of a CYP3A4 substrate drug, orprescribing treatment of the CYP3A4 substrate drug to be delayed, for atleast 2-21 days after stopping the posaconazole regimen, and then (e)treating with a CYP3A4 substrate drug. In other embodiments, the methodsinclude (a) treating a patient with multiple doses of posaconazole, (b)not treating the patient with the CYP3A4 substrate drug during theposaconazole regimen, (c) stopping the posaconazole regimen; and (d) forat least about 2-21 days after stopping the posaconazole regimen,treating the patient with the CYP3A4 substrate drug at a dose which isno more than about 50% of the reference dose of the CYP3A4 substratedrug (e.g., an amount in the range of about 10% to about 50%, or about10% to about 90%, of the reference dose, as described above). Thedisease or condition treated with the CYP3A4 substrate drug can includeany disease or condition described herein or for which CYP3 substratedrug is administered. In some embodiments, the disease or condition isselected from the group consisting of schizophrenia in adults andadolescents (13 to 17 years), depressive episodes associated withBipolar I Disorder (bipolar depression) in adults, as monotherapy or asadjunctive therapy with lithium or valproate, chronic angina, erectiledysfunction (ED), benign prostatic hyperplasia (BPH), and pulmonaryarterial hypertension (PAH) (WHO Group 1) to improve exercise ability.In some embodiments, the time period for delaying administration of theCYP3A4 substrate drug, or the time period during which the CYP3A4substrate drug is administered at no more than 50% of the referencedose, is greater than about 21 days, e.g., for patients with one or morephysiological characteristics described herein.

Other particular embodiments are provided herein below:

1. A method of treating a patient who has previously been administered atherapeutically effective regimen of posaconazole, with a CYP3A4substrate drug contraindicated for concomitant administration with astrong CYP3A4 inhibitor, said method comprising:

first treating the patient, or prescribing a first treatment to begin,with the CYP3A4 substrate drug at least 2-21 days after stoppingadministration of posaconazole.

2. The method of embodiment 1, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, and colchicine.

3. The method of embodiment 2, wherein the CYP3A4 substrate drug islurasidone.

4. The method of embodiment 2, wherein the CYP3A4 substrate drug isranolazine.

5. The method of embodiment 2, wherein the CYP3A4 substrate drug istadalafil.

6. The method of any of embodiments 1-5, wherein the patient is obese.

7. The method of embodiment 6, wherein the patient has at least one ofthe following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

8. The method of any of embodiments 1-7, wherein the CYP3A4 substratedrug is ranolazine, and the AUC of ranolazine is maintained at a levelof no more than about 150% of a normal baseline AUC of ranolazine.

9. The method of any of embodiments 1-7, wherein the CYP3A4 substratedrug is ranolazine, and the C_(max) of ranolazine is maintained at alevel of no more than about 150% of a normal baseline C_(max) ofranolazine.

10. The method of any of embodiments 1-7, wherein the CYP3A4 substratedrug is lurasidone, and the AUC of lurasidone is maintained at a levelof no more than about 216% of a normal baseline AUC of lurasidone.

11. The method of any of embodiments 1-7, wherein the CYP3A4 substratedrug is lurasidone, and the C_(max) of lurasidone is maintained at alevel of no more than about 210% of a normal baseline C_(max) oflurasidone.

12. The method of any of embodiments 1-7, wherein the CYP3A4 substratedrug is tadalafil, and the AUC of tadalafil is maintained at a level ofno more than about 410% of a normal baseline AUC of tadalafil.

13. The method of any of embodiments 1-7, wherein the CYP3A4 substratedrug is tadalafil, and the a C_(max) of tadalafil is maintained at alevel of no more than about 120% of a normal baseline C_(max) oftadalafil.

14. The method of embodiments 1-10, wherein the patient is a poor orintermediate CYP3A4 metabolizer.

15. A method of treating a patient with a CYP3A4 substrate drugcontraindicated for concomitant administration with a strong CYP3A4inhibitor, comprising:

treating or prescribing a therapeutically effective amount of a CYP3A4substrate drug to a patient in need thereof,

wherein:

said patient has previously been administered a therapeuticallyeffective regimen of posaconazole, and

for at least about 2-21 days after discontinuation of the posaconazoleregimen, said patient is treated with the CYP3A4 substrate drug is at adose which is no more than about 50% of the reference dose.

16. The method of embodiment 15, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, and colchicine.

17. The method of embodiment 16, wherein the CYP3A4 substrate drug islurasidone.

18. The method of embodiment 16, wherein the CYP3A4 substrate drug isranolazine.

19. The method of embodiment 16, wherein the CYP3A4 substrate drug istadalafil.

20. The method of any of embodiments 15-19, wherein the patient isobese.

21. The method of embodiment 20, wherein the patient has at least one ofthe following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

22. The method of any of embodiments 15-21, wherein the CYP3A4 substratedrug is ranolazine, and the AUC of ranolazine is maintained at a levelof no more than about a normal baseline AUC of ranolazine to about 150%of the normal baseline AUC of ranolazine.

23. The method of any of embodiments 15-21, wherein the CYP3A4 substratedrug is ranolazine, and the C_(max) of ranolazine is maintained at alevel of no more than about a normal baseline C_(max) of ranolazine toabout 150% of the normal baseline C_(max) of ranolazine.

24. The method of any of embodiments 15-21, wherein the CYP3A4 substratedrug is lurasidone, and the AUC of lurasidone is maintained at a levelof no more than about a normal baseline AUC of lurasidone to about 216%of the normal baseline AUC of lurasidone.

25. The method of any of embodiments 15-21, wherein the CYP3A4 substratedrug is lurasidone, and the C_(max) of lurasidone is maintained at alevel of no more than about a normal baseline C_(max) of lurasidone toabout 210% of the normal baseline C_(max) of lurasidone.

26. The method of any of embodiments 15-21, wherein the CYP3A4 substratedrug is tadalafil, and the AUC of tadalafil is maintained at a level ofno more than about 410% of a normal baseline AUC of tadalafil.

27. The method of any of embodiments 15-21, wherein the CYP3A4 substratedrug is tadalafil, and the a C_(max) of tadalafil is maintained at alevel of no more than about 120% of a normal baseline C_(max) oftadalafil.

28. The method of embodiments 15-27, wherein the patient is a poor orintermediate CYP3A4 metabolizer.

29. The method of embodiment 15, wherein the CYP3A4 substrate drug isranolazine and the daily dose is no more than about 500 mg for at leastabout 2-21 days after discontinuation of the posaconazole regimen.

30. A method of treating a disease or condition in a patient with aCYP3A4 substrate drug which is contraindicated for concomitant use witha strong CYP3A4 inhibitor, wherein the patient is also in need oftreatment with posaconazole, comprising:

(a) treating a patient with a therapeutically effective regimen ofposaconazole;

(b) not treating the patient with the CYP3A4 substrate drug during theposaconazole regimen, and for at least 2-21 days after stopping theposaconazole regimen; and then

(c) treating, or prescribing treatment to begin, with a therapeuticallyeffective amount of the CYP3A4 substrate drug;

wherein the disease or condition treated with the CYP3A4 substrate drugis selected from the group consisting of schizophrenia in adults andadolescents (13 to 17 years), depressive episodes associated withBipolar I Disorder (bipolar depression) in adults, as monotherapy or asadjunctive therapy with lithium or valproate, chronic angina, cysticfibrosis in patients 6 years and older who are homozygous for theF508del mutation in the CFTR gene, chronic lymphocytic leukemia inpatients with 17p deletion, who have received at least one priortherapy, unresectable or metastatic liposarcoma or leiomyosarcoma inpatients who received a prior anthracycline-containing regimen, advancedor metastatic breast cancer in postmenopausal women with hormonereceptor (HR)-positive, human epidermal growth factor receptor 2(HER2)-negative advanced or metastatic breast cancer, negative advancedor metastatic breast cancer in combination with an aromatase inhibitorfor postmenopausal women, Duchenne muscular dystrophy (DMD), secondaryhyperparathyroidism (HPT) in patients with chronic kidney disease (CKD)on dialysis, hypercalcemia in patients with parathyroid carcinoma or inpatients with primary HPT for who parathyroidectomy would be indicatedon the basis of serum calcium levels, but who are unable to undergoparathyroidectomy, hallucinations and delusions associated withParkinson's disease psychosis, schizophrenia, acute manic or mixedepisodes associated with bipolar I disorder, chronic hepatitis C (CHC)infection as a component of a combination antiviral treatment regimenwith peginterferon alfa and ribavirin in HCV genotype 1 infectedsubjects with compensated liver disease, postmenopausal women withadvanced hormone receptor-positive, HER2-negative breast cancer(advanced HR+BC), e.g., in combination with exemestane after failure oftreatment with letrozole or anastrozole, progressive neuroendocrinetumors of pancreatic origin (PNET), progressive, well-differentiated,non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) orlung origin that are unresectable, locally advanced or metastatic,advanced renal cell carcinoma (RCC), e.g., after failure of treatmentwith sunitinib or sorafenib, renal angiomyolipoma and tuberous sclerosiscomplex (TSC), not requiring immediate surgery, TSC in patients who havesubependymal giant cell astrocytoma (SEGA) that require therapeuticintervention but are not candidates for surgical resection, type 2diabetes mellitus in adults as an adjunct to diet and exercise toimprove glycemic control, major depressive disorder (MDD), thromboticcardiovascular events (e.g., cardiovascular death, myocardialinfarction, or stroke) in patients with acute coronary syndrome (ACS),stroke and systemic embolism in patients with nonvalvular atrialfibrillation, deep vein thrombosis (DVT), which may lead to pulmonaryembolism (PE) in patients who have undergone hip or knee replacementsurgery, DVT, PE, recurrent DVT and PE following initial therapy,moderate to severe active rheumatoid arthritis in patients who have hadinadequate response or tolerance to methotrexate, acute migraine with orwithout aura, chronic phase and accelerated phase Philadelphiachromosome positive chronic myeloid leukemia (Ph+CML) in newly diagnosedpatients or in patients resistant to or intolerant to prior therapy thatincluded imatinib, atrial fibrillation (AF) in patients with a historyof paroxysmal or persistent AF or atrial flutter (AFK), who are in sinusrhythm or will be cardioverted, asthma in patients aged 4 years andolder, airflow obstruction and reducing exacerbations in patients withchronic obstructive pulmonary disease, erectile dysfunction (ED), benignprostatic hyperplasia (BPH), pulmonary arterial hypertension (PAH) (WHOGroup 1) to improve exercise ability, gout flares, FamilialMediterranean fever antiretroviral therapy, anxiety disorders, panicdisorders, seizures, insomnia, hypertension, cardiovascular disease,hyperlipidemia, cancer, such as primary kidney cancer, advanced primaryliver cancer, radioactive iodine resistant advanced thyroid carcinoma,renal cell carcinoma, imatinib-resistant gastrointestinal stromal tumor,mantle cell lymphoma in patients who have received at least one priortherapy, chronic lymphocytic leukemia/small lymphocytic lymphoma,chronic lymphocytic leukemia/small lymphocytic lymphoma with 17pdeletion, Waldenstrom's macroglobulinemia, marginal zone lymphoma whorequire systemic therapy and have received at least one prioranti-CD20-based therapy, unresectable or metastatic melanoma with a BRAFV600E or V600K mutation, allergies, and transplantation.

31. The method of embodiment 30, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, and colchicine.

32. The method of embodiment 31, wherein the CYP3A4 substrate drug islurasidone.

33. The method of embodiment 31, wherein the CYP3A4 substrate drug isranolazine.

34. The method of embodiment 31, wherein the CYP3A4 substrate drug istadalafil.

35. The method of any of embodiments 30-34, wherein the patient isobese.

36. The method of embodiment 35, wherein the patient has at least one ofthe following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

37. The method of any of embodiments 30-36, wherein the CYP3A4 substratedrug is ranolazine, and the AUC of ranolazine is maintained at a levelof no more than about 150% of a normal baseline AUC of ranolazine.

38. The method of any of embodiments 30-36, wherein the CYP3A4 substratedrug is ranolazine, and the C_(max) of ranolazine is maintained at alevel of no more than about 150% of a normal baseline C_(max) ofranolazine.

39. The method of any of embodiments 30-36, wherein the CYP3A4 substratedrug is lurasidone, and the AUC of lurasidone is maintained at a levelof no more than about 216% of a normal baseline AUC of lurasidone.

40. The method of any of embodiments 30-36, wherein the CYP3A4 substratedrug is lurasidone, and the C_(max) of lurasidone is maintained at alevel of no more than about 210% of a normal baseline C_(max) oflurasidone.

41. The method of any of embodiments 30-36, wherein the CYP3A4 substratedrug is tadalafil, and the AUC of tadalafil is maintained at a level ofno more than about 410% of a normal baseline AUC of tadalafil.

42. The method of any of embodiments 30-36, wherein the CYP3A4 substratedrug is tadalafil, and the a C_(max) of tadalafil is maintained at alevel of no more than about 120% of a normal baseline C_(max) oftadalafil.

43. The method of any of embodiments 30-42, wherein the patient is apoor or intermediate CYP3A4 metabolizer.

44. A method of treating a disease or condition in a patient with aCYP3A4 substrate drug which is contraindicated for concomitant use witha strong CYP3A4 inhibitor, wherein the patient is also in need oftreatment with posaconazole, comprising:

(a) treating a patient with a therapeutically effective regimen ofposaconazole to the patient;

(b) not administering the CYP3A4 substrate drug during theadministration of the posaconazole regimen;

(c) for at least about 2-21 days after stopping the posaconazoleregimen, treating the patient with, or prescribing, the CYP3A4 substratedrug at a dose which is no more than about 50% of the reference dose;

wherein the disease or condition treated with the CYP3A4 substrate drugis selected from the group consisting of schizophrenia in adults andadolescents (13 to 17 years), depressive episodes associated withBipolar I Disorder (bipolar depression) in adults, as monotherapy or asadjunctive therapy with lithium or valproate, chronic angina, cysticfibrosis in patients 6 years and older who are homozygous for theF508del mutation in the CFTR gene, chronic lymphocytic leukemia inpatients with 17p deletion, who have received at least one priortherapy, unresectable or metastatic liposarcoma or leiomyosarcoma inpatients who received a prior anthracycline-containing regimen, advancedor metastatic breast cancer in postmenopausal women with hormonereceptor (HR)-positive, human epidermal growth factor receptor 2(HER2)-negative advanced or metastatic breast cancer, negative advancedor metastatic breast cancer in combination with an aromatase inhibitorfor postmenopausal women, Duchenne muscular dystrophy (DMD), secondaryhyperparathyroidism (HPT) in patients with chronic kidney disease (CKD)on dialysis, hypercalcemia in patients with parathyroid carcinoma or inpatients with primary HPT for who parathyroidectomy would be indicatedon the basis of serum calcium levels, but who are unable to undergoparathyroidectomy, hallucinations and delusions associated withParkinson's disease psychosis, schizophrenia, acute manic or mixedepisodes associated with bipolar I disorder, chronic hepatitis C (CHC)infection as a component of a combination antiviral treatment regimenwith peginterferon alfa and ribavirin in HCV genotype 1 infectedsubjects with compensated liver disease, postmenopausal women withadvanced hormone receptor-positive, HER2-negative breast cancer(advanced HR+BC), e.g., in combination with exemestane after failure oftreatment with letrozole or anastrozole, progressive neuroendocrinetumors of pancreatic origin (PNET), progressive, well-differentiated,non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) orlung origin that are unresectable, locally advanced or metastatic,advanced renal cell carcinoma (RCC), e.g., after failure of treatmentwith sunitinib or sorafenib, renal angiomyolipoma and tuberous sclerosiscomplex (TSC), not requiring immediate surgery, TSC in patients who havesubependymal giant cell astrocytoma (SEGA) that require therapeuticintervention but are not candidates for surgical resection, type 2diabetes mellitus in adults as an adjunct to diet and exercise toimprove glycemic control, major depressive disorder (MDD), thromboticcardiovascular events (e.g., cardiovascular death, myocardialinfarction, or stroke) in patients with acute coronary syndrome (ACS),stroke and systemic embolism in patients with nonvalvular atrialfibrillation, deep vein thrombosis (DVT), which may lead to pulmonaryembolism (PE) in patients who have undergone hip or knee replacementsurgery, DVT, PE, recurrent DVT and PE following initial therapy,moderate to severe active rheumatoid arthritis in patients who have hadinadequate response or tolerance to methotrexate, acute migraine with orwithout aura, chronic phase and accelerated phase Philadelphiachromosome positive chronic myeloid leukemia (Ph+CML) in newly diagnosedpatients or in patients resistant to or intolerant to prior therapy thatincluded imatinib, atrial fibrillation (AF) in patients with a historyof paroxysmal or persistent AF or atrial flutter (AFK), who are in sinusrhythm or will be cardioverted, asthma in patients aged 4 years andolder, airflow obstruction and reducing exacerbations in patients withchronic obstructive pulmonary disease, erectile dysfunction (ED), benignprostatic hyperplasia (BPH), pulmonary arterial hypertension (PAH) (WHOGroup 1) to improve exercise ability, mantle cell lymphoma in patientswho have received at least one prior therapy, chronic lymphocyticleukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/smalllymphocytic lymphoma with 17p deletion, Waldenström's macroglobulinemia,marginal zone lymphoma who require systemic therapy and have received atleast one prior anti-CD20-based therapy, unresectable or metastaticmelanoma with a BRAF V600E or V600K mutation, gout flares, and FamilialMediterranean fever.

45. The method of embodiment 44, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, and colchicine.

46. The method of embodiment 45, wherein the CYP3A4 substrate drug islurasidone.

47. The method of embodiment 45, wherein the CYP3A4 substrate drug isranolazine.

48. The method of embodiment 45, wherein the CYP3A4 substrate drug istadalafil.

49. The method of any of embodiments 44-48, wherein the patient isobese.

50. The method of embodiment 49, wherein the patient has at least one ofthe following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

51. The method of any of embodiments 44-50, wherein the CYP3A4 substratedrug is ranolazine, and the AUC of ranolazine is maintained at a levelof no more than about a normal baseline AUC of ranolazine to about 150%of the normal baseline AUC of ranolazine.

52. The method of any of embodiments 44-50, wherein the CYP3A4 substratedrug is ranolazine, and the C_(max) of ranolazine is maintained at alevel of no more than about a normal baseline C_(max) of ranolazine toabout 150% of the normal baseline C_(max) of ranolazine.

53. The method of any of embodiments 44-50, wherein the CYP3A4 substratedrug is lurasidone, and the AUC of lurasidone is maintained at a levelof no more than about a normal baseline AUC of lurasidone to about 216%of the normal baseline AUC of lurasidone.

54. The method of any of embodiments 44-50, wherein the CYP3A4 substratedrug is lurasidone, and the C_(max) of lurasidone is maintained at alevel of no more than about a normal baseline C_(max) of lurasidone toabout 210% of the normal baseline C_(max) of lurasidone.

55. The method of any of embodiments 44-50, wherein the CYP3A4 substratedrug is tadalafil, and the AUC of tadalafil is maintained at a level ofno more than about 410% of a normal baseline AUC of tadalafil.

56. The method of any of embodiments 44-50, wherein the CYP3A4 substratedrug is tadalafil, and the a C_(max) of tadalafil is maintained at alevel of no more than about 120% of a normal baseline C_(max) oftadalafil.

57. The method of embodiments 44-56, wherein the patient is a poor orintermediate CYP3A4 metabolizer.

58. The method of embodiment 44, wherein the CYP3A4 substrate drug isranolazine and the daily dose is no more than about 500 mg for at leastabout 2-21 days after discontinuation of the posaconazole regimen.

59. A method of treating a patient in need thereof comprising delaying afirst treatment of a CYP3A4 substrate drug until about 2-21 days afterstopping administration of posaconazole.

60. The method of embodiment 59, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, and colchicine.

61. The method of embodiment 60, wherein the CYP3A4 substrate drug islurasidone.

62. The method of embodiment 60, wherein the CYP3A4 substrate drug isranolazine.

63. The method of embodiment 60, wherein the CYP3A4 substrate drug istadalafil.

64. The method of any of embodiments 59-63, wherein the patient isobese.

65. The method of embodiment 64, wherein the patient has at least one ofthe following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

66. The method of any of embodiments 59-65, wherein the CYP3A4 substratedrug is ranolazine, and the AUC of ranolazine is maintained at a levelof no more than about 150% of a normal baseline AUC of ranolazine.

67. The method of any of embodiments 59-65, wherein the CYP3A4 substratedrug is ranolazine, and the C_(max) of ranolazine is maintained at alevel of no more than about 150% of a normal baseline C_(max) ofranolazine.

68. The method of any of embodiments 59-65, wherein the CYP3A4 substratedrug is lurasidone, and the AUC of lurasidone is maintained at a levelof no more than about 216% of a normal baseline AUC of lurasidone.

68. The method of any of embodiments 59-65, wherein the CYP3A4 substratedrug is lurasidone, and the C_(max) of lurasidone is maintained at alevel of no more than about 210% of a normal baseline C_(max) oflurasidone.

69. The method of any of embodiments 59-65, wherein the CYP3A4 substratedrug is tadalafil, and the AUC of tadalafil is maintained at a level ofno more than about 410% of a normal baseline AUC of tadalafil.

70. The method of any of embodiments 59-65, wherein the CYP3A4 substratedrug is tadalafil, and the a C_(max) of tadalafil is maintained at alevel of no more than about 120% of a normal baseline C_(max) oftadalafil.

80. The method of embodiments 59-70, wherein the patient is a poor orintermediate CYP3A4 metabolizer.

81. A method of treating a patient previously on posaconazole with aCYP3A4 substrate drug which is contraindicated for concomitant use witha strong CYP3A4 inhibitor comprising, delaying a first treatment, orprescribing a first treatment to be delayed, of the CYP3A4 substratedrug for at least about 2-21 days after posaconazole administration hasceased.

82. The method of embodiment 81, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, and colchicine.

83. The method of embodiment 82, wherein the CYP3A4 substrate drug islurasidone.

84. The method of embodiment 82, wherein the CYP3A4 substrate drug isranolazine.

85. The method of embodiment 45, wherein the CYP3A4 substrate drug istadalafil.

86. The method of any of embodiments 81-85, wherein the patient isobese.

87. The method of embodiment 86, wherein the patient has at least one ofthe following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

88. The method of any of embodiments 81-87, wherein the CYP3A4 substratedrug is ranolazine, and the AUC of ranolazine is maintained at a levelof no more than about 150% of a normal baseline AUC of ranolazine.

89. The method of any of embodiments 81-87, wherein the CYP3A4 substratedrug is ranolazine, and the C_(max) of ranolazine is maintained at alevel of no more than about 150% of a normal baseline C_(max) ofranolazine.

90. The method of any of embodiments 81-87, wherein the CYP3A4 substratedrug is lurasidone, and the AUC of lurasidone is maintained at a levelof no more than about 216% of a normal baseline AUC of lurasidone.

91. The method of any of embodiments 81-87, wherein the CYP3A4 substratedrug is lurasidone, and the C_(max) of lurasidone is maintained at alevel of no more than about 210% of a normal baseline C_(max) oflurasidone.

92. The method of any of embodiments 81-87, wherein the CYP3A4 substratedrug is tadalafil, and the AUC of tadalafil is maintained at a level ofno more than about 410% of a normal baseline AUC of tadalafil.

93. The method of any of embodiments 81-87, wherein the CYP3A4 substratedrug is tadalafil, and the a Cmax of tadalafil is maintained at a levelof no more than about 120% of a normal baseline Cmax of tadalafil.

94. The method of embodiments 81-93, wherein the patient is a poor orintermediate CYP3A4 metabolizer.

95. A method of treating a patient with a CYP3A4 substrate drugcontraindicated for concomitant use with a strong CYP3A4 inhibitor,comprising treating the patient, or prescribing a treatment of, theCYP3A4 substrate drug at a dose which is less than or equal to about 50%of the reference dose for a period of at least about 2-21 days afterstopping administration of posaconazole.

96. The method of embodiment 95, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, and colchicine.

97. The method of embodiment 96, wherein the CYP3A4 substrate drug islurasidone.

98. The method of embodiment 96, wherein the CYP3A4 substrate drug isranolazine.

99. The method of embodiment 96, wherein the CYP3A4 substrate drug istadalafil.

100. The method of any of embodiments 95-99, wherein the patient isobese.

101. The method of embodiment 100, wherein the patient has at least oneof the following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

102. The method of any of embodiments 95-101, wherein the CYP3A4substrate drug is ranolazine, and the AUC of ranolazine is maintained ata level of no more than about a normal baseline AUC of ranolazine toabout 150% of the normal baseline AUC of ranolazine.

103. The method of any of embodiments 95-101, wherein the CYP3A4substrate drug is ranolazine, and the C_(max) of ranolazine ismaintained at a level of no more than about a normal baseline C_(max) ofranolazine to about 150% of the normal baseline C_(max) of ranolazine.

104. The method of any of embodiments 95-101, wherein the CYP3A4substrate drug is lurasidone, and the AUC of lurasidone is maintained ata level of no more than about a normal baseline AUC of lurasidone toabout 216% of the normal baseline AUC of lurasidone.

105. The method of any of embodiments 95-101, wherein the CYP3A4substrate drug is lurasidone, and the C_(max) of lurasidone ismaintained at a level of no more than about a normal baseline C_(max) oflurasidone to about 210% of the normal baseline C_(max) of lurasidone.

106. The method of any of embodiments 95-101, wherein the CYP3A4substrate drug is tadalafil, and the AUC of tadalafil is maintained at alevel of no more than about 410% of a normal baseline AUC of tadalafil.

107. The method of any of embodiments 95-101, wherein the CYP3A4substrate drug is tadalafil, and the a C_(max) of tadalafil ismaintained at a level of no more than about 120% of a normal baselineC_(max) of tadalafil.

108. The method of embodiments 95-107, wherein the patient is a poor orintermediate CYP3A4 metabolizer.

109. The method of embodiment 95, wherein the CYP3A4 substrate drug isranolazine and the daily dose is no more than about 500 mg for at leastabout 2-21 days after discontinuation of the posaconazole regimen.

110. A method of treating a disease or condition in a patient with aCYP3A4 substrate drug which is contraindicated for concomitant use witha strong CYP3A4 inhibitor, comprising:

(a) delaying a first treatment, or prescribing a delay of the firsttreatment, of the CYP3A4 substrate drug for at least 2-21 days afterstopping administration of posaconazole; and then(b) administering the CYP3A4 substrate drug;

wherein the disease or condition treated with the CYP3A4 substrate drugis selected from the group consisting of schizophrenia in adults andadolescents (13 to 17 years), depressive episodes associated withBipolar I Disorder (bipolar depression) in adults, as monotherapy or asadjunctive therapy with lithium or valproate, chronic angina, cysticfibrosis in patients 6 years and older who are homozygous for theF508del mutation in the CFTR gene, chronic lymphocytic leukemia inpatients with with 17p deletion, who have received at least one priortherapy, unresectable or metastatic liposarcoma or leiomyosarcoma inpatients who received a prior anthracycline-containing regimen, advancedor metastatic breast cancer in postmenopausal women with hormonereceptor (HR)-positive, human epidermal growth factor receptor 2(HER2)-negative advanced or metastatic breast cancer, negative advancedor metastatic breast cancer in combination with an aromatase inhibitorfor postmenopausal women, Duchenne muscular dystrophy (DMD), secondaryhyperparathyroidism (HPT) in patients with chronic kidney disease (CKD)on dialysis, hypercalcemia in patients with parathyroid carcinoma or inpatients with primary HPT for who parathyroidectomy would be indicatedon the basis of serum calcium levels, but who are unable to undergoparathyroidectomy, hallucinations and delusions associated withParkinson's disease psychosis, schizophrenia, acute manic or mixedepisodes associated with bipolar I disorder, chronic hepatitis C (CHC)infection as a component of a combination antiviral treatment regimenwith peginterferon alfa and ribavirin in HCV genotype 1 infectedsubjects with compensated liver disease, postmenopausal women withadvanced hormone receptor-positive, HER2-negative breast cancer(advanced HR+BC), e.g., in combination with exemestane after failure oftreatment with letrozole or anastrozole, progressive neuroendocrinetumors of pancreatic origin (PNET), progressive, well-differentiated,non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) orlung origin that are unresectable, locally advanced or metastatic,advanced renal cell carcinoma (RCC), e.g., after failure of treatmentwith sunitinib or sorafenib, renal angiomyolipoma and tuberous sclerosiscomplex (TSC), not requiring immediate surgery, TSC in patients who havesubependymal giant cell astrocytoma (SEGA) that require therapeuticintervention but are not candidates for surgical resection, type 2diabetes mellitus in adults as an adjunct to diet and exercise toimprove glycemic control, major depressive disorder (MDD), thromboticcardiovascular events (e.g., cardiovascular death, myocardialinfarction, or stroke) in patients with acute coronary syndrome (ACS),stroke and systemic embolism in patients with nonvalvular atrialfibrillation, deep vein thrombosis (DVT), which may lead to pulmonaryembolism (PE) in patients who have undergone hip or knee replacementsurgery, DVT, PE, recurrent DVT and PE following initial therapy,moderate to severe active rheumatoid arthritis in patients who have hadinadequate response or tolerance to methotrexate, acute migraine with orwithout aura, chronic phase and accelerated phase Philadelphiachromosome positive chronic myeloid leukemia (Ph+CML) in newly diagnosedpatients or in patients resistant to or intolerant to prior therapy thatincluded imatinib, atrial fibrillation (AF) in patients with a historyof paroxysmal or persistent AF or atrial flutter (AFK), who are in sinusrhythm or will be cardioverted, asthma in patients aged 4 years andolder, airflow obstruction and reducing exacerbations in patients withchronic obstructive pulmonary disease, erectile dysfunction (ED), benignprostatic hyperplasia (BPH), pulmonary arterial hypertension (PAH) (WHOGroup 1) to improve exercise ability, gout flares, FamilialMediterranean fever, antiretroviral therapy, anxiety disorders, panicdisorders, seizures, insomnia, hypertension, cardiovascular disease,hyperlipidemia, cancer, such as primary kidney cancer, advanced primaryliver cancer, radioactive iodine resistant advanced thyroid carcinoma,renal cell carcinoma, imatinib-resistant gastrointestinal stromal tumor,mantle cell lymphoma in patients who have received at least one priortherapy, chronic lymphocytic leukemia/small lymphocytic lymphoma,chronic lymphocytic leukemia/small lymphocytic lymphoma with 17pdeletion, Waldenström's macroglobulinemia, marginal zone lymphoma whorequire systemic therapy and have received at least one prioranti-CD20-based therapy, unresectable or metastatic melanoma with a BRAFV600E or V600K mutation, allergies, and transplantation.

111. The method of embodiment 110, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, and colchicine.

112. The method of embodiment 111, wherein the CYP3A4 substrate drug islurasidone.

113. The method of embodiment 111, wherein the CYP3A4 substrate drug isranolazine.

114. The method of embodiment 111, wherein the CYP3A4 substrate drug istadalafil.

115. The method of any of embodiments 110-114, wherein the patient isobese.

116. The method of embodiment 115, wherein the patient has at least oneof the following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

117. The method of any of embodiments 110-116, wherein the CYP3A4substrate drug is ranolazine, and the AUC of ranolazine is maintained ata level of no more than about 150% of a normal baseline AUC ofranolazine.

118. The method of any of embodiments 110-116, wherein the CYP3A4substrate drug is ranolazine, and the C_(max) of ranolazine ismaintained at a level of no more than about 150% of a normal baselineC_(max) of ranolazine.

119. The method of any of embodiments 110-116, wherein the CYP3A4substrate drug is lurasidone, and the AUC of lurasidone is maintained ata level of no more than about 216% of a normal baseline AUC oflurasidone.

120. The method of any of embodiments 110-116, wherein the CYP3A4substrate drug is lurasidone, and the C_(max) of lurasidone ismaintained at a level of no more than about 210% of a normal baselineC_(max) of lurasidone.

121. The method of any of embodiments 110-116, wherein the CYP3A4substrate drug is tadalafil, and the AUC of tadalafil is maintained at alevel of no more than about 410% of a normal baseline AUC of tadalafil.

122. The method of any of embodiments 110-116, wherein the CYP3A4substrate drug is tadalafil, and the a C_(max) of tadalafil ismaintained at a level of no more than about 120% of a normal baselineC_(max) of tadalafil.

123. The method of embodiments 110-122, wherein the patient is a poor orintermediate CYP3A4 metabolizer.

124. A method of treating a patient with a CYP3A4 substrate drug whichis contraindicated for concomitant use with a strong CYP3A4 inhibitor,comprising:

(a) delaying a first treatment, or prescribing a delay in the firsttreatment, of the CYP3A4 substrate drug for at least about 2-21 daysafter stopping administration of the posaconazole regimen; and then

(d) treating the patient with the CYP3A4 substrate drug at a dose whichis less than or equal to about 50% of the reference dose for at leastabout 2-21 days after stopping administration of the posaconazoleregimen;

wherein the disease or condition treated with the CYP3A4 substrate drugis selected from the group consisting of schizophrenia in adults andadolescents (13 to 17 years), depressive episodes associated withBipolar I Disorder (bipolar depression) in adults, as monotherapy or asadjunctive therapy with lithium or valproate, chronic angina, cysticfibrosis in patients 6 years and older who are homozygous for theF508del mutation in the CFTR gene, chronic lymphocytic leukemia inpatients with 17p deletion, who have received at least one priortherapy, unresectable or metastatic liposarcoma or leiomyosarcoma inpatients who received a prior anthracycline-containing regimen, advancedor metastatic breast cancer in postmenopausal women with hormonereceptor (HR)-positive, human epidermal growth factor receptor 2(HER2)-negative advanced or metastatic breast cancer, negative advancedor metastatic breast cancer in combination with an aromatase inhibitorfor postmenopausal women, Duchenne muscular dystrophy (DMD), secondaryhyperparathyroidism (HPT) in patients with chronic kidney disease (CKD)on dialysis, hypercalcemia in patients with parathyroid carcinoma or inpatients with primary HPT for who parathyroidectomy would be indicatedon the basis of serum calcium levels, but who are unable to undergoparathyroidectomy, hallucinations and delusions associated withParkinson's disease psychosis, schizophrenia, acute manic or mixedepisodes associated with bipolar I disorder, chronic hepatitis C (CHC)infection as a component of a combination antiviral treatment regimenwith peginterferon alfa and ribavirin in HCV genotype 1 infectedsubjects with compensated liver disease, postmenopausal women withadvanced hormone receptor-positive, HER2-negative breast cancer(advanced HR+BC), e.g., in combination with exemestane after failure oftreatment with letrozole or anastrozole, progressive neuroendocrinetumors of pancreatic origin (PNET), progressive, well-differentiated,non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) orlung origin that are unresectable, locally advanced or metastatic,advanced renal cell carcinoma (RCC), e.g., after failure of treatmentwith sunitinib or sorafenib, renal angiomyolipoma and tuberous sclerosiscomplex (TSC), not requiring immediate surgery, TSC in patients who havesubependymal giant cell astrocytoma (SEGA) that require therapeuticintervention but are not candidates for surgical resection, type 2diabetes mellitus in adults as an adjunct to diet and exercise toimprove glycemic control, major depressive disorder (MDD), thromboticcardiovascular events (e.g., cardiovascular death, myocardialinfarction, or stroke) in patients with acute coronary syndrome (ACS),stroke and systemic embolism in patients with nonvalvular atrialfibrillation, deep vein thrombosis (DVT), which may lead to pulmonaryembolism (PE) in patients who have undergone hip or knee replacementsurgery, DVT, PE, recurrent DVT and PE following initial therapy,moderate to severe active rheumatoid arthritis in patients who have hadinadequate response or tolerance to methotrexate, acute migraine with orwithout aura, chronic phase and accelerated phase Philadelphiachromosome positive chronic myeloid leukemia (Ph+CML) in newly diagnosedpatients or in patients resistant to or intolerant to prior therapy thatincluded imatinib, atrial fibrillation (AF) in patients with a historyof paroxysmal or persistent AF or atrial flutter (AFK), who are in sinusrhythm or will be cardioverted, asthma in patients aged 4 years andolder, airflow obstruction and reducing exacerbations in patients withchronic obstructive pulmonary disease, erectile dysfunction (ED), benignprostatic hyperplasia (BPH), pulmonary arterial hypertension (PAH) (WHOGroup 1) to improve exercise ability, gout flares, FamilialMediterranean fever, antiretroviral therapy, anxiety disorders, panicdisorders, seizures, insomnia, hypertension, cardiovascular disease,hyperlipidemia, cancer, such as primary kidney cancer, advanced primaryliver cancer, radioactive iodine resistant advanced thyroid carcinoma,renal cell carcinoma, imatinib-resistant gastrointestinal stromal tumor,mantle cell lymphoma in patients who have received at least one priortherapy, chronic lymphocytic leukemia/small lymphocytic lymphoma,chronic lymphocytic leukemia/small lymphocytic lymphoma with 17pdeletion, Waldenström's macroglobulinemia, marginal zone lymphoma whorequire systemic therapy and have received at least one prioranti-CD20-based therapy, unresectable or metastatic melanoma with a BRAFV600E or V600K mutation, allergies, and transplantation.

125. The method of embodiment 124, wherein said CYP3A4 substrate drug isselected from the group consisting of lurasidone, ranolazine,lumacaftor/ivacaftor, venetoclax, trabectedin, ribociclib succinate,deflazacort, cinacalcet hydrochloride, pimavanserin tartrate,aripiprazole lauroxil, cariprazine hydrochloride, simeprevir sodium,everolimus, saxagliptin hydrochloride, saxagliptin/metforminhydrochloride, ticagrelor, vilazodone hydrochloride, apixaban,tofacitinib citrate, eletriptan hydrobromide, nilotinib hydrochloridemonohydrate, dronedarone hydrochloride, fluticasonepropionate/salmeterol xinafoate, rivaroxaban, tadalafil, ibrutinib,cobimetinib, and colchicine.

126. The method of embodiment 125, wherein the CYP3A4 substrate drug islurasidone.

127. The method of embodiment 125, wherein the CYP3A4 substrate drug isranolazine.

128. The method of embodiment 125, wherein the CYP3A4 substrate drug istadalafil.

129. The method of any of embodiments 124-128, wherein the patient isobese.

130. The method of embodiment 129, wherein the patient has at least oneof the following characteristics:

i) BMI of at least about 35;

ii) % IBW of at least about 150%;

iii) waist size greater than about 42 inches;

iv) % body fat greater than about 40%;

v) total body fat greater than about 40 kg; and

vi) medically diagnosed as obese.

131. The method of any of embodiments 124-132, wherein the CYP3A4substrate drug is ranolazine, and the AUC of ranolazine is maintained ata level of no more than about a normal baseline AUC of ranolazine toabout 150% of the normal baseline AUC of ranolazine.

132. The method of any of embodiments 124-132, wherein the CYP3A4substrate drug is ranolazine, and the C_(max) of ranolazine ismaintained at a level of no more than about a normal baseline C_(max) ofranolazine to about 150% of the normal baseline C_(max) of ranolazine.

133. The method of any of embodiments 124-132, wherein the CYP3A4substrate drug is lurasidone, and the AUC of lurasidone is maintained ata level of no more than about a normal baseline AUC of lurasidone toabout 216% of the normal baseline AUC of lurasidone.

134. The method of any of embodiments 124-132, wherein the CYP3A4substrate drug is lurasidone, and the C_(max) of lurasidone ismaintained at a level of no more than about a normal baseline C_(max) oflurasidone to about 210% of the normal baseline C_(max) of lurasidone.

135. The method of any of embodiments 124-132, wherein the CYP3A4substrate drug is tadalafil, and the AUC of tadalafil is maintained at alevel of no more than about 410% of a normal baseline AUC of tadalafil.

136. The method of any of embodiments 124-132, wherein the CYP3A4substrate drug is tadalafil, and the a Cmax of tadalafil is maintainedat a level of no more than about 120% of a normal baseline Cmax oftadalafil.

137. The method of any one of embodiments 134-136, wherein the patientis a poor or intermediate CYP3A4 metabolizer.

EXAMPLES Example 1. Pharmacokinetic Studies with Posaconazole andLurasidone

Inventors studied 6 obese male and female subjects (ages 18-50, BMI>35)taking Posaconazole oral tablets (300 mg qd) and Lurasidone (20 mg qd).Body weights and BMI measurements for the 6 subjects are provided belowin Table 1.

TABLE 1 Subject Demographics Subject # Weight (kg) BMI (kg/m²) 101-001111.8 45 101-002 136.8 44.4 101-005 137.7 51.2 101-007 103.7 36.8101-008 122.3 39.8 101-010 120.0 43.9

Subjects were dosed with Lurasidone alone on Day 1, then subsequentlydosed to steady-state Posaconazole levels, with a loading dose of 300 mgtwice a day on Day 2 and 300 mg once a day thereafter over a period of14 days. Posaconazole administration was then stopped and Lurasidone (20mg qd) administered 2, 4, and 6 days after administration had ceased(studies days 17, 19, and 21 respectively). Lurasidone AUC was measuredfor 24 hours after each administration. Table 2 shows subject LurasidoneAUC levels 2, 4 and 6 days after Posaconazole was stopped, PosaconazoleAUC levels 2, 4, and 6 days after Posaconazole was stopped, and theratio of post-Posaconazole Lurasidone AUC to the baseline Lurasidone AUCmeasured before Posaconazole treatment:

TABLE 2 Posaconazole Lurasidone Lurasidone AUC AUC Ratio Subject DataAUC (ng * h/mL) (ng * h/mL) relative to Day 1 BMI Weight Subject Day 1Day 17 Day 19 Day 21 Day 17 Day 19 Day 21 Day 17 Day 19 Day 21 (kg/m²)(kg) HMS001 101- 92.8 284 234.4 204.5 2886 2019 1365 3.06 2.53 2.20 45.0111.8 001 DES005 101- 26 167.3 186 168 2512 1954 1563 6.43 7.15 6.4651.2 137.7 005 TRB007 101- 38.3 173.8 89.5 124.7 824 542 285 4.54 2.343.26 36.8 103.7 007 NNJ010 101- 71 211.7 163 226 4551 3688 3081 2.982.30 3.18 43.9 120.0 010 KDH002 101- 110 195.5 146 186.3 1299 626 2841.78 1.33 1.69 44.4 136.8 002 DTG008 101- 45.6 57 36.2 27.8 190 78 311.25 0.79 0.61 39.8 122.3 008

Table 3 compares Lurasidone AUC levels after Posaconazole treatment tobaseline Lurasidone AUC levels.

TABLE 3 Lurasidone Levels vs. Base Line Days After Posaconazole WasCeased Day 2 Day 4 Day 6 Mean 3.3x 2.7x 2.9x Min 1.3x 0.8x 0.6x Max 6.4x7.2x 6.5x Median 3.0x 2.3x 2.7x

As shown above in Table 3, the post-Posaconazole treatment mean AUCratios of Lurasidone are about 3 times higher than the baseline. Thisdata indicates that Posaconazole accumulates in obese subjects, andresults in significantly higher Lurasidone AUC levels compared tobaseline levels measured before Posaconazole treatment.

The AUC measurements from two patients (DTG008 and KDH002) indicatesthat these patients were non-compliant with the Posaconazole treatmentregimen, and the corresponding AUC measurements were removed from thestudy. The results are shown below in Table 4.

TABLE 4 Lurasidone Levels vs. Base Line Days After Posaconazole WasCeased Excluding DTG008 & KDH002 Day 2 Day 4 Day 6 Mean 4.3x 3.6x 3.8xMin 3.0x 2.3x 2.2x Max 6.4x 7.2x 6.5x Median 3.8x 2.4x 3.2x

These results indicate that post-Posaconazole treatment mean AUC ratiovalues for Lurasidone are in the range of from 3.6-4.3× for 2-6 daysafter ceasing Posaconazole treatment.

In conclusion, the results from the clinical trials reported in Example1 indicate that the Posaconazole accumulates in the body of obesepatients after treatment has stopped, and patients should delay a firstdose of Lurasidone or reduce the first dose of Lurasidone to achievesafe blood plasma levels of Lurasidone.

1.-9. (canceled)
 10. A method of treating a patient for chronic angina with ranolazine, wherein the patient is receiving treatment with posaconazole, comprising: (a) stopping posaconazole treatment; (b) delaying administration of ranolazine after step (a) for up to about 7 days; then (c) administering a dose of ranolazine that is not more than about 50% of a reference dose of ranolazine, for about 5-21 days.
 11. The method of claim 10, wherein said administration of ranolazine in step (c) is for about 5-14 days.
 12. The method of claim 11, wherein said delaying in step (b) is up to one day.
 13. The method of claim 10, wherein said administration of ranolazine in step (c) is for about 5-10 days.
 14. The method of claim 13, wherein the delay in step (b) is for up to one day.
 15. The method of claim 13, wherein the patient is not obese.
 16. The method of claim 15, wherein said administration of ranolazine in step (c) is for about 7 days.
 17. The method of claim 16, wherein said delaying in step (b) is for one day.
 18. The method of claim 10, wherein said administration of ranolazine in step (c) is for about 10-14 days.
 19. The method of claim 18, wherein the delay in step (b) is for up to one day.
 20. The method of claim 18, wherein the patient has at least one characteristic selected from the group consisting of the following: i) BMI of at least about 35; ii) % IBW of at least about 150%; iii) waist size greater than about 42 inches; iv) % body fat greater than about 40%; v) total body fat greater than about 40 kg, and; vi) medically diagnosed as obese.
 21. The method of claim 18, wherein said administering of ranolazine in step (c) is for about 12 days.
 22. The method of claim 21, wherein said delaying in step (b) is for up to one day.
 23. The method of claim 10, wherein after step (c) an AUC of ranolazine is no more than about 150% of a normal baseline AUC of the ranolazine reference dose.
 24. The method of claim 23, wherein the reference dose of ranolazine is 1000 mg.
 25. The method of claim 10, wherein the reference dose of ranolazine is 1000 mg.
 26. The method of claim 10, wherein: the reference dose of ranolazine is 1000 mg; said delaying in step (b) is up to one day; and said administering of ranolazine in step (c) is for about 5-14 days.
 27. The method of claim 10, wherein: the reference dose of ranolazine is 1000 mg; said delaying in step (b) is up to one day; said administering of ranolazine in step (c) is for about 5-14 days; and the patient has at least one characteristic selected from the group consisting of the following: i) BMI of at least about 35; ii) % IBW of at least about 150%; iii) waist size greater than about 42 inches; iv) % body fat greater than about 40%; v) total body fat greater than about 40 kg, and; vi) medically diagnosed as obese. 